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1
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Jülke EM, Beck-Sickinger AG. Peptide therapeutics: current status and future opportunity with focus on nose-to-brain delivery☆. Peptides 2025; 188:171404. [PMID: 40222598 DOI: 10.1016/j.peptides.2025.171404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 04/15/2025]
Abstract
Peptide drugs are a highly diverse group of therapeutic agents. Over the last decade, more than 40 peptides have been approved for clinical use. They target different structures, ranging from G protein-coupled receptors (GPCRs) to pathogens and are used to treat a variety of indications, including metabolic disorders, genetic diseases, acute illnesses and more. Structurally, peptide therapeutics are a heterogeneous class. This diversity allows them to bridge the gap between small molecules and biologics. However, limited metabolic stability and bioavailability must be addressed. Strategies to improve the half-life include backbone and sequence modification, cyclization and the addition of stabilizing moieties. Great strides have been made in recent years towards achieving sufficient drug uptake for oral application have been achieved within recent years. However, these methods require specialized peptide design or involve permeabilization of the gastrointestinal tract. Consequently, other routes of administration are being explored. One promising approach is the nasal application of peptides. This method can be used for systemic uptake, but also allows for direct nose-to-brain delivery of compounds. While successful nose-to-brain delivery is already used in the clinic, the underlining mechanisms are poorly understood. Strategies for rational optimization are needed to make this method more applicable to a wider range of compounds. Overall, approved peptide therapeutics cover a wide range of applications and have demonstrated a growing and novel potential in recent drug discovery.
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Affiliation(s)
- Eva-Maria Jülke
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, Leipzig 04103, Germany
| | - Annette G Beck-Sickinger
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, Leipzig 04103, Germany.
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2
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Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, Coghlan MP, D'Alessio D, Deacon CF, DelPrato S, Douros JD, Drucker DJ, Figueredo Burgos NS, Flatt PR, Finan B, Gimeno RE, Gribble FM, Hayes MR, Hölscher C, Holst JJ, Knerr PJ, Knop FK, Kusminski CM, Liskiewicz A, Mabilleau G, Mowery SA, Nauck MA, Novikoff A, Reimann F, Roberts AG, Rosenkilde MM, Samms RJ, Scherer PE, Seeley RJ, Sloop KW, Wolfrum C, Wootten D, DiMarchi RD, Tschöp MH. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab 2025; 95:102118. [PMID: 40024571 PMCID: PMC11931254 DOI: 10.1016/j.molmet.2025.102118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. MAJOR CONCLUSIONS Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.
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Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany.
| | - Alice Adriaenssens
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Matthew P Coghlan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - David D'Alessio
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Carolyn F Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano DelPrato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | | | - Daniel J Drucker
- The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natalie S Figueredo Burgos
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Brian Finan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Fiona M Gribble
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Hölscher
- Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Patrick J Knerr
- Indianapolis Biosciences Research Institute, Indianapolis, IN, USA
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine M Kusminski
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arkadiusz Liskiewicz
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France
| | | | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany
| | - Frank Reimann
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Anna G Roberts
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Ricardo J Samms
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Philip E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kyle W Sloop
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
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3
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Jayakody T, Budagoda DK, Mendis K, Dilshan WD, Bethmage D, Dissasekara R, Dawe GS. Biased agonism in peptide-GPCRs: A structural perspective. Pharmacol Ther 2025; 269:108806. [PMID: 39889970 DOI: 10.1016/j.pharmthera.2025.108806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 12/13/2024] [Accepted: 01/15/2025] [Indexed: 02/03/2025]
Abstract
G protein-coupled receptors (GPCRs) are dynamic membrane receptors that transduce extracellular signals to the cell interior by forming a ligand-receptor-effector (ternary) complex that functions via allosterism. Peptides constitute an important class of ligands that interact with their cognate GPCRs (peptide-GPCRs) to form the ternary complex. "Biased agonism", a therapeutically relevant phenomenon exhibited by GPCRs owing to their allosteric nature, has also been observed in peptide-GPCRs, leading to the development of selective therapeutics with fewer side effects. In this review, we have focused on the structural basis of signalling bias at peptide-GPCRs of classes A and B, and reviewed the therapeutic relevance of bias at peptide-GPCRs, with the hope of contributing to the discovery of novel biased peptide drugs.
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Affiliation(s)
- Tharindunee Jayakody
- Department of Chemistry, University of Colombo, P.O. Box 1490, Colombo 00300, Sri Lanka
| | | | - Krishan Mendis
- Department of Chemistry, University of Colombo, P.O. Box 1490, Colombo 00300, Sri Lanka
| | | | - Duvindu Bethmage
- Department of Chemistry, University of Colombo, P.O. Box 1490, Colombo 00300, Sri Lanka
| | - Rashmi Dissasekara
- Department of Chemistry, University of Colombo, P.O. Box 1490, Colombo 00300, Sri Lanka; The Graduate School, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Gavin Stewart Dawe
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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4
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Cary BP, Hager MV, Mariam Z, Morris RK, Belousoff MJ, Deganutti G, Sexton PM, Wootten D, Gellman SH. Prolonged signaling of backbone-modified glucagon-like peptide- 1 analogues with diverse receptor trafficking. Proc Natl Acad Sci U S A 2025; 122:e2407574122. [PMID: 40168114 PMCID: PMC12002026 DOI: 10.1073/pnas.2407574122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 02/07/2025] [Indexed: 04/03/2025] Open
Abstract
Signal duration and subcellular location are emerging as important facets of G protein-coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cyclic adenosine monophosphate (cAMP) upon activation by the native hormone, GLP-1. cAMP production continues after the hormone-receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from (S,S)-trans-2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryoelectron microscopy structures of two GLP-1 analogues bound to the GLP-1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R:Gs complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profiles. Our results advance understanding of the structural underpinnings of receptor activation and introduce tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation.
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Affiliation(s)
- Brian P. Cary
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI53706
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
- Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
| | - Marlies V. Hager
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI53706
| | - Zamara Mariam
- Centre for Health and Life Sciences, Coventry University, CoventryCV1 5FB, United Kingdom
| | - Rylie K. Morris
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI53706
| | - Matthew J. Belousoff
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
- Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
| | - Giuseppe Deganutti
- Centre for Health and Life Sciences, Coventry University, CoventryCV1 5FB, United Kingdom
| | - Patrick M. Sexton
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
- Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
| | - Denise Wootten
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
- Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC3052, Australia
| | - Samuel H. Gellman
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI53706
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5
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Collins J, Farnsworth NL. Active targeting of type 1 diabetes therapies to pancreatic beta cells using nanocarriers. Diabetologia 2025; 68:692-703. [PMID: 39847085 DOI: 10.1007/s00125-024-06356-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/21/2024] [Indexed: 01/24/2025]
Abstract
Type 1 diabetes is an autoimmune disease characterised by the destruction of pancreatic beta cells, resulting in lifelong insulin dependence. Although exogenous insulin can maintain glycaemic control, this approach does not protect residual or replacement pancreatic beta cells from immune-mediated death. Current therapeutics designed to protect functional beta cell mass or promote beta cell proliferation and regeneration can have off-target effects, resulting in higher dose requirements and adverse side effects. Targeted drug delivery using nanocarriers has demonstrated potential for overcoming these limitations. The critical bottleneck limiting the development of beta cell-targeted therapies is a lack of highly specific beta cell markers. This review provides an overview of the use of nanocarriers for cell-targeted delivery and the current state of the field of beta cell targeting. Technologies such as systematic evolution of ligands by exponential enrichment (SELEX) aptamer selection, phage display screening, and omics datasets from human samples are highlighted as tools to identify novel beta cell-specific targets that can be combined with nanocarriers for targeted delivery of therapeutics. Ultimately, beta cell-targeted therapies using nanocarriers present a unique opportunity to develop tailored treatments for each stage of type 1 diabetes with the goal of providing individuals with treatment options that prevent further progression or reverse the course of the disease.
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Affiliation(s)
- Jillian Collins
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, USA
| | - Nikki L Farnsworth
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, USA.
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6
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Wong MT, Lin PH, Lin WC, Peng CJ, Wright JD, Lee HJ, Chu HM, Lim C, Chang TW. 2FA-Platform Generates Dual Fatty Acid-Conjugated GLP-1 Receptor Agonist TE-8105 with Enhanced Diabetes, Obesity, and NASH Efficacy Compared to Semaglutide. J Med Chem 2025; 68:6178-6192. [PMID: 40044142 PMCID: PMC11956005 DOI: 10.1021/acs.jmedchem.4c02153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 03/28/2025]
Abstract
Conjugating two fatty acids (2FAs) to peptide drugs can improve pharmacokinetics and therapeutic effects. However, optimizing FA spacing, chain combination, and attachment site to simultaneously enhance albumin binding and drug efficacy remains challenging. We introduce a multiarm linker technology enabling precise control of 2FA spacing, composition, and attachment. By applying this technology to a modified glucagon-like peptide-1 (GLP-1) and screening various 2FA-GLP-1 conjugates differing in linkage, linker, and FA properties for improved albumin affinity, pharmacokinetics, and pharmacodynamics, TE-8105 emerged as a promising candidate. TE-8105 outperformed semaglutide, showing improved long-term glycemic control, weight loss, and liver health in diabetic mice, and dose-dependent weight loss and favorable body composition changes in obese mice. A distinct advantage of TE-8105 over semaglutide is its low-dose reduction of liver steatosis and improvement of liver health in nonalcoholic steatohepatitis mice. The multiarm linker technology provides a versatile platform for developing improved 2FA-peptide therapeutics.
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Affiliation(s)
- Mun-Teng Wong
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Pei-Hsuan Lin
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Wei-Chen Lin
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Chi-Jiun Peng
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Jon D. Wright
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Hui-Ju Lee
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Hsing-Mao Chu
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Carmay Lim
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Tse Wen Chang
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
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7
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Gare CL, White AM, Malins LR. From lead to market: chemical approaches to transform peptides into therapeutics. Trends Biochem Sci 2025:S0968-0004(25)00024-6. [PMID: 40011178 DOI: 10.1016/j.tibs.2025.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/21/2025] [Accepted: 01/29/2025] [Indexed: 02/28/2025]
Abstract
Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the 'drug-like' properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.
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Affiliation(s)
- Caitlin L Gare
- Research School of Chemistry, Australian National University, Canberra 2601, Australian Capital Territory, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra 2601, Australian Capital Territory, Australia
| | - Andrew M White
- Research School of Chemistry, Australian National University, Canberra 2601, Australian Capital Territory, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra 2601, Australian Capital Territory, Australia
| | - Lara R Malins
- Research School of Chemistry, Australian National University, Canberra 2601, Australian Capital Territory, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra 2601, Australian Capital Territory, Australia.
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8
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Krieger JP, Daniels D, Lee S, Mastitskaya S, Langhans W. Glucagon-Like Peptide-1 Links Ingestion, Homeostasis, and the Heart. Compr Physiol 2025; 15:e7. [PMID: 39887844 PMCID: PMC11790259 DOI: 10.1002/cph4.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 02/01/2025]
Abstract
Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."
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Affiliation(s)
- Jean-Philippe Krieger
- Jean-Philippe Krieger, Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, Winterthurerstr. 260, 8057 Zurich
| | - Derek Daniels
- Department of Biological Sciences and the Center for Ingestive Behavior Research, University at Buffalo, the State University of New York, Buffalo NY 14260 USA
| | - Shin Lee
- Shin J. Lee, Neurimmune AG, Wagistrasse 18, 8952 Schlieren, Switzerland
| | - Svetlana Mastitskaya
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Dept. of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland
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9
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El-Solh AA, Gould E, Aibangbee K, Jimerson T, Hartling R. Current perspectives on the use of GLP-1 receptor agonists in obesity-related obstructive sleep apnea: a narrative review. Expert Opin Pharmacother 2025; 26:51-62. [PMID: 39621418 DOI: 10.1080/14656566.2024.2437525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/23/2024] [Accepted: 11/29/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION Traditionally, obstructive sleep apnea (OSA) management has focused on continuous positive airway pressure therapy, oral appliances, and in some cases, surgical interventions. However, these treatments do not directly address the underlying metabolic issues contributing to OSA. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes management, have demonstrated substantial efficacy in promoting weight. AREAS COVERED This review aims to summarize the potential impact of liraglutide, semaglutide, and tirzepatide in managing obese patients with OSA. EXPERT OPINION The introduction of GLP-1 RAs has gained attention not only for their ability to produce significant and sustained weight loss but also for their potential to improve OSA symptoms by reducing fat deposition around the upper airway and decreasing systemic inflammation. Emerging clinical trials suggest that GLP-1 RAs may enhance traditional OSA treatments, offering an integrated approach targeting the root cause of obesity in OSA. Additionally, GLP-1 RAs may provide benefits for other obesity-related comorbidities, including hypertension and cardiovascular disease, which are commonly associated with OSA. The future integration of GLP-1 RAs into OSA treatment protocols could mark a paradigm shift toward more comprehensive management strategies, ultimately improving patient outcomes in this complex patient population.
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Affiliation(s)
- Ali A El-Solh
- Sleep Disorders Research Center, Western New York Healthcare System, Buffalo, NY, USA
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, Buffalo, NY, USA
| | - Erin Gould
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Keziah Aibangbee
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Tanya Jimerson
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Rebecca Hartling
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
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10
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Holst JJ. Annual Prize Lecture 2024: Endogenous physiological mechanisms as basis for the treatment of obesity and type 2 diabetes. J Physiol 2024; 602:6613-6629. [PMID: 39520693 DOI: 10.1113/jp287461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
In 1964, it was proven that postprandial insulin secretion is largely regulated by gut hormones and, in 1973, it was proposed that a gut hormone would also regulate appetite and food intake. Several gut hormones were tested for metabolic actions with disappointing results until the discovery of the proglucagon derivative, glucagon-like peptide-1 (GLP-1). This peptide from the distal intestine has preserved activity on insulin secretion in people with type 2 diabetes and turned out to regulate both secretion and motility in the gastrointestinal tract and importantly, appetite and food intake, thus functioning as an efficient 'ileal brake' hormone. However, the natural hormone acts predominantly via sensory afferent systems and is extremely rapidly removed from the circulation by enzymatic degradation and renal elimination, and increasing the doses merely results in nausea and vomiting. Lipidation of analogs turned out to provide both stability and limit renal elimination, and very slow up-titration of dosing improves tolerance. Indeed, the most recent agonists may near-normalize glycaemic control in type 2 diabetes, may cause weight losses of up to 25% of body weight, and significantly reduce cardiovascular risk, effects that resemble those of bariatric surgery. Thus, a solution to one of the most serious health problems of modern civilization, the increased morbidity and mortality of the metabolic syndrome, may be addressed by mobilization of one of the body's own regulatory mechanisms.
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Affiliation(s)
- Jens Juul Holst
- The NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, The Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Copenhagen N, Denmark
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11
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Holst JJ. GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab 2024; 6:1866-1885. [PMID: 39160334 DOI: 10.1038/s42255-024-01113-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/17/2024] [Indexed: 08/21/2024]
Abstract
The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15-25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy.
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Affiliation(s)
- Jens Juul Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences. Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
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12
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Liu QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol (Lausanne) 2024; 15:1431292. [PMID: 39114288 PMCID: PMC11304055 DOI: 10.3389/fendo.2024.1431292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.
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Affiliation(s)
- Qiyuan Keith Liu
- MedStar Medical Group, MedStar Montgomery Medical Center, Olney, MD, United States
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13
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Zhang C, Yang X, Wu L, Liu F, Dong K, Guo C, Gong L, Dong G, Shi Y, Gu Z, Liu X, Liu S, Wu J, Su F. Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity. ACS Pharmacol Transl Sci 2024; 7:1426-1437. [PMID: 38751623 PMCID: PMC11091969 DOI: 10.1021/acsptsci.4c00054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/01/2024] [Accepted: 04/09/2024] [Indexed: 05/18/2024]
Abstract
Protein tyrosine phosphatase 1B (PTP1B) and TC-PTP can function in a coordinated manner to regulate diverse biological processes including insulin and leptin signaling, T-cell activation, and tumor antigen presentation, which makes them potential targets for several therapeutic applications. We have previously demonstrated that the lipidated BimBH3 peptide analogues were a new class of promising PTP1B inhibitors with once-weekly antidiabetic potency. Herein, we chemically synthesized two series of BimBH3 analogues via site-specific modification and studied their structure-activity relationship. The screened analogues S2, S6, A2-14, A2-17, A2-20, and A2-21 exhibited an improved PTP1B/TC-PTP dual inhibitory activity and achieved good stability in the plasma of mice and dogs, which indicated long-acting potential. In mouse models of type 2 diabetes mellitus (T2DM), the selected analogues S6, S7, A2-20, and A2-21 with an excellent target activity and plasma stability generated once-weekly therapeutic potency for T2DM at lower dosage (0.5 μmol/kg). In addition, evidence was provided to confirm the cell permeability and targeted enrichment of the BimBH3 analogues. In summary, we report here that site-specific modification and long fatty acid conjugation afforded cell-permeable peptidomimetic analogues of BimBH3 with enhanced stability, in vivo activity, and long-acting pharmacokinetic profile. Our findings could guide the further optimization of BimBH3 analogues and provide a proof-of-concept for PTP1B/TC-PTP targeting as a new therapeutic approach for T2DM, which may facilitate the discovery and development of alternative once-weekly anti-T2DM drug candidates.
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Affiliation(s)
- Chuanliang Zhang
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
- School
of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, China
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Xianmin Yang
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Lijuan Wu
- School
of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, China
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Fei Liu
- Joincare
Pharmaceutical Group Industry Co., Ltd, Shenzhen 518000, China
| | - Kehong Dong
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Chuanlong Guo
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Liyan Gong
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Guozhen Dong
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Yiying Shi
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Zongwen Gu
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
| | - Xiaochun Liu
- School
of Medicine and Pharmacy, Ocean University
of China, Qingdao 266003, China
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Shan Liu
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Juan Wu
- Marine
Biomedical Research Institute, Ocean University
of China, Qingdao 266003, China
| | - Feng Su
- State
Key Laboratory Base of Eco-chemical Engineering, College of Chemical
Engineering, Qingdao University of Science
and Technology, Qingdao 266042, China
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14
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Abubakar M, Nama L, Ansari MA, Ansari MM, Bhardwaj S, Daksh R, Syamala KLV, Jamadade MS, Chhabra V, Kumar D, Kumar N. GLP-1/GIP Agonist as an Intriguing and Ultimate Remedy for Combating Alzheimer's Disease through its Supporting DPP4 Inhibitors: A Review. Curr Top Med Chem 2024; 24:1635-1664. [PMID: 38803170 DOI: 10.2174/0115680266293416240515075450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 04/14/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer's disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer's disease. AIM This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD. METHODS This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD. RESULTS The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions. CONCLUSION With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer's patients.
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Affiliation(s)
- Mohammad Abubakar
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Lokesh Nama
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Mohammad Arif Ansari
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Mohammad Mazharuddin Ansari
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Shivani Bhardwaj
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Rajni Daksh
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Katta Leela Venkata Syamala
- Department of Regulatory and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Mohini Santosh Jamadade
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Vishal Chhabra
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Dileep Kumar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
- Department of Entomology, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
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15
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Kraihammer M, von Guggenberg E, Hörmann AA, Gabriel M, Decristoforo C. Automated production of [ 68Ga]Ga-DOTA-exendin-4 via fractionated radionuclide generator elution on a cassette based synthesis module. Nucl Med Biol 2023; 124-125:108381. [PMID: 37634398 DOI: 10.1016/j.nucmedbio.2023.108381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND PET/CT imaging of glucagon-like peptide receptor 1 has recently filled a gap in reliably diagnosing insulinoma through non-invasive means. 68Ga-labelled derivatives of exendin-4 show high sensitivity as well as sufficient serum stability to enable routine clinical application. Here, we provide data for automated production of [68Ga][Nle14,Lys40(Ahx-DOTA-Ga)NH2]exendin-4 ([68Ga]Ga-DOTA-exendin-4) on a cassette based synthesis module (Modular-Lab PharmTracer, Eckert & Ziegler) using commercially available cassettes in combination with an approved 68Ge/68Ga generator (GalliaPharm, Eckert & Ziegler). This setup ensured high reproducibility as well as low radiation burden for the production team. Quality control including determination of radiochemical purity was performed by RP-HPLC using a water/0.1 % TFA/acetonitrile gradient on a C18 column. A modified TLC system with ammonium acetate & methanol as mobile phase and a novel limit test for determination of polysorbate 80 content in the final formulation are also described in this study. MAIN FINDINGS Reliable yields as well as high molar activity for patient use were only achieved using a fractionated elution approach. Batch data showed radiochemical purity of >93 % as determined by RP-HPLC and TLC as well as good stability over 2 h post production. Testing for polysorbate 80 confirmed a concentration <1 mg/mL in the final product solution. Specifications for routine production were established based on existing Pharmacopeia monographs for other radiopharmaceuticals and were validated with 5 master batches. CONCLUSION The described synthesis method enables reproducible, automated in-house production of [68Ga]Ga-DOTA-exendin-4 for routine clinical application.
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Affiliation(s)
- Martin Kraihammer
- Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; Department of Nuclear Medicine and Endocrinology, Kepler University Hospital, Krankenhausstrasse 9, 4021 Linz, Austria
| | - Elisabeth von Guggenberg
- Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Anton Amadeus Hörmann
- Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Michael Gabriel
- Department of Nuclear Medicine and Endocrinology, Kepler University Hospital, Krankenhausstrasse 9, 4021 Linz, Austria
| | - Clemens Decristoforo
- Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
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16
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Valverde-Pozo J, Paredes JM, Widmann TJ, Griñan-Lison C, Ceccarelli G, Gioiello A, Garcia-Rubiño ME, Marchal JA, Alvarez-Pez JM, Talavera EM. Ratiometric Two-Photon Near-Infrared Probe to Detect DPP IV in Human Plasma, Living Cells, Human Tissues, and Whole Organisms Using Zebrafish. ACS Sens 2023; 8:1064-1075. [PMID: 36847549 PMCID: PMC10043939 DOI: 10.1021/acssensors.2c02025] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
DPP IV, otherwise known as CD26 lymphocyte T surface antigen, is a transmembrane glycoprotein also found in circulation in the blood. It plays an important role in several processes like glucose metabolism and T-cell stimulation. Moreover, it is overexpressed in renal, colon, prostate, and thyroid human carcinoma tissues. It can also serve as a diagnostic in patients with lysosomal storage diseases. The biological and clinical importance of having readouts for the activity of this enzyme, in physiological and disease conditions, has led us to design a near-infrared (NIR) fluorimetric probe that also has the characteristics of being ratiometric and excitable by two simultaneous NIR photons. The probe consists of assembling an enzyme recognition group (Gly-Pro) (Mentlein, 1999; Klemann et al., 2016) on the two-photon (TP) fluorophore (derivative of dicyanomethylene-4H-pyran, DCM-NH2) disturbing its NIR characteristic internal charge transfer (ICT) emission spectrum. When the dipeptide group is released by the DPP IV-specific enzymatic action, the donor-acceptor DCM-NH2 is restored, forming a system that shows high ratiometric fluorescence output. With this new probe, we have been able to detect, quickly and efficiently, the enzymatic activity of DPP IV in living cells, human tissues, and whole organisms, using zebrafish. In addition, due to the possibility of being excited by two photons, we can avoid the autofluorescence and subsequent photobleaching that the raw plasma has when it is excited by visible light, achieving detection of the activity of DPP IV in that medium without interference.
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Affiliation(s)
- Javier Valverde-Pozo
- Nanoscopy-UGR Laboratory, Department of Physical Chemistry, Faculty of Pharmacy, Unidad de Excelencia en Quimica Aplicada a Biomedicina y Medioambiente (UEQ), University of Granada, C. U. Cartuja, 18071 Granada, Spain
| | - Jose M Paredes
- Nanoscopy-UGR Laboratory, Department of Physical Chemistry, Faculty of Pharmacy, Unidad de Excelencia en Quimica Aplicada a Biomedicina y Medioambiente (UEQ), University of Granada, C. U. Cartuja, 18071 Granada, Spain
| | - Thomas J Widmann
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain
| | - Carmen Griñan-Lison
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria (ibs.GRANADA), 18012 Granada, Spain
- UGC de Oncología Médica, Complejo Hospitalario de Jaen, 23007 Jaen, Spain
| | - Giada Ceccarelli
- Laboratory of Medicinal and Advanced Synthetic Chemistry (Lab MASC), Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
| | - Antimo Gioiello
- Laboratory of Medicinal and Advanced Synthetic Chemistry (Lab MASC), Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
| | - M Eugenia Garcia-Rubiño
- Nanoscopy-UGR Laboratory, Department of Physical Chemistry, Faculty of Pharmacy, Unidad de Excelencia en Quimica Aplicada a Biomedicina y Medioambiente (UEQ), University of Granada, C. U. Cartuja, 18071 Granada, Spain
| | - Juan A Marchal
- Instituto de Investigación Biosanitaria (ibs.GRANADA), 18012 Granada, Spain
- Centre for Biomedical Research (CIBM), Biopathology and Regenerative Medicine Institute (IBIMER), University of Granada, 18100 Granada, Spain
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, 18016 Granada, Spain
| | - Jose M Alvarez-Pez
- Nanoscopy-UGR Laboratory, Department of Physical Chemistry, Faculty of Pharmacy, Unidad de Excelencia en Quimica Aplicada a Biomedicina y Medioambiente (UEQ), University of Granada, C. U. Cartuja, 18071 Granada, Spain
| | - Eva M Talavera
- Nanoscopy-UGR Laboratory, Department of Physical Chemistry, Faculty of Pharmacy, Unidad de Excelencia en Quimica Aplicada a Biomedicina y Medioambiente (UEQ), University of Granada, C. U. Cartuja, 18071 Granada, Spain
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Viljoen A, Bain SC. Glucagon-Like Peptide 1 Therapy: From Discovery to Type 2 Diabetes and Beyond. Endocrinol Metab (Seoul) 2023; 38:25-33. [PMID: 36740965 PMCID: PMC10008669 DOI: 10.3803/enm.2022.1642] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 12/28/2022] [Indexed: 02/07/2023] Open
Abstract
The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes and/or obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimer's disease.
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Affiliation(s)
- Adie Viljoen
- Borthwick Diabetes Research Centre, Lister Hospital (East and North Hertfordshire NHS Trust), Stevenage, UK
- Corresponding author: Adie Viljoen. Borthwick Diabetes Research Centre, Lister Hospital (East and North Hertfordshire NHS Trust), Stevenage, SG1 4AB, UK Tel: +44-1438-285-972, Fax: +44-1438-285-972, E-mail:
| | - Stephen C. Bain
- Department of Biomedical Sciences, Swansea University Medical School, Swansea, UK
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18
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Abstract
Obesity is a major public health issue with an increasing prevalence worldwide. Excess body fat is associated with various comorbidities, as well as increased overall mortality risk. The benefits of weight loss are evident by the reductions in morbidity and mortality. The foundation for most weight loss programs involves strict lifestyle modification, including dietary change and exercise. Unfortunately, many individuals struggle with weight loss and chronic weight management due to difficulty adhering to long-term lifestyle modification and the metabolic adaptations that promote weight regain. The use of adjunctive pharmacotherapy has been employed to help patients not only achieve greater weight loss than lifestyle modification alone but also to assist with long-term weight management. Historically, antiobesity drugs have produced only modest weight loss and required at least once daily administration. Glucagon-like peptide-1 (GLP-1), a hormone with significant effects on glycemic control and weight regulation, has been explored for use as adjunctive pharmacotherapy for weight loss. Semaglutide, a GLP-1 receptor agonist, was recently approved by the Food and Drug Administration for chronic weight management in adults with obesity or who are overweight. The approval came after the publication of the Semaglutide Treatment Effect in People with Obesity clinical trials. In these 68-week trials, semaglutide 2.4 mg was associated with significantly greater weight loss compared to placebo. Semaglutide differs from other GLP-1 receptor agonists by having a longer half-life and producing greater weight loss. This article provides an overview of the discovery and mechanism of action of semaglutide 2.4 mg, and the clinical trials that led to its approval.
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Affiliation(s)
- Joel Novograd
- From the New York Medical College (student) Valhalla, NY
| | - Jaime Mullally
- Department of Medicine, Division of Endocrinology, New York Medical College/Westchester Medical Center, Valhalla, NY
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19
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Zhang H, Dong M, Yuan S, Jin W. Oral glucagon-like peptide 1 analogue ameliorates glucose intolerance in db/db mice. Biotechnol Lett 2022; 44:1149-1162. [PMID: 36006576 DOI: 10.1007/s10529-022-03288-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 08/04/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVES We constructed a recombinant oral GLP-1 analogue in Lactococcus lactis (L. lactis) and evaluated its physiological functions. RESULTS In silico docking suggested the alanine at position 8 substituted with serine (A8SGLP-1) reduced binding of DPP4, which translated to reduced cleavage by DPP4 with minimal changes in stability. This was further confirmed by an in vitro enzymatic assay which showed that A8SGLP-1 significantly increased half-life upon DPP4 treatment. In addition, recombinant L. lactis (LL-A8SGLP-1) demonstrated reduced fat mass with no changes in body weight, significant improvement of random glycemic control and reduced systemic inflammation compared with WT GLP-1 in db/db mice. CONCLUSION LL-A8SGLP-1 adopted in live biotherapeutic products reduce blood glucose in db/db mice without affecting its function.
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Affiliation(s)
- Hanlin Zhang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 1 West Beichen Rd. No. 5, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Meng Dong
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 1 West Beichen Rd. No. 5, Beijing, 100101, China
| | - Shouli Yuan
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 1 West Beichen Rd. No. 5, Beijing, 100101, China
| | - Wanzhu Jin
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 1 West Beichen Rd. No. 5, Beijing, 100101, China.
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20
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Palani A, Nawrocki AR, Orvieto F, Bianchi E, Mandić E, Pessi A, Huang C, Deng Q, Toussaint N, Walsh E, Reddy V, Ashley E, He H, Mumick S, Hawes B, Marsh D, Erion M, Nargund R, Carrington PE. Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes. ACS Med Chem Lett 2022; 13:1248-1254. [PMID: 35978682 PMCID: PMC9377002 DOI: 10.1021/acsmedchemlett.2c00217] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/15/2022] [Indexed: 01/12/2023] Open
Abstract
Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials.
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Affiliation(s)
- Anandan Palani
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Andrea R. Nawrocki
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Federica Orvieto
- Peptide
Chemistry Unit, Peptides and Small Molecules R&D, IRBM SpA, Via Pontina, Km 30.600, 00071 Roma, Italy
| | - Elisabetta Bianchi
- Peptide
Chemistry Unit, Peptides and Small Molecules R&D, IRBM SpA, Via Pontina, Km 30.600, 00071 Roma, Italy
| | - Emanuela Mandić
- Peptide
Chemistry Unit, Peptides and Small Molecules R&D, IRBM SpA, Via Pontina, Km 30.600, 00071 Roma, Italy
| | | | - Chunhui Huang
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Qiaolin Deng
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Nathalie Toussaint
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Erika Walsh
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Vijay Reddy
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Eric Ashley
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Huaibing He
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Sheena Mumick
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Brian Hawes
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Donald Marsh
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Mark Erion
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Ravi Nargund
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
| | - Paul E. Carrington
- Merck
& Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States
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21
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Mahapatra MK, Karuppasamy M, Sahoo BM. Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes. Rev Endocr Metab Disord 2022; 23:521-539. [PMID: 34993760 PMCID: PMC8736331 DOI: 10.1007/s11154-021-09699-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2021] [Indexed: 11/22/2022]
Abstract
Semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, is available as monotherapy in both subcutaneous as well as oral dosage form (first approved oral GLP-1 receptor agonist). It has been approved as a second line treatment option for better glycaemic control in type 2 diabetes and currently under scrutiny for anti-obesity purpose. Semaglutide has been proved to be safe in adults and elderly patients with renal or hepatic disorders demanding no dose modification. Cardiovascular (CV) outcome trials established that it can reduce various CV risk factors in patients with established CV disorders. Semaglutide is well tolerated with no risk of hypoglycaemia in monotherapy but suffers from gastrointestinal adverse effects. A large population affected with COVID-19 infection were diabetic; therefore use of semaglutide in diabetes as well as CV patients would be very much supportive in maintaining health care system during this pandemic situation. Hence, this peptidic drug can be truly considered as a quintessential of GLP-1 agonists for management of type 2 diabetes.
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Affiliation(s)
- Manoj Kumar Mahapatra
- Kanak Manjari Institute of Pharmaceutical Sciences, Rourkela, 769015, Odisha, India.
| | - Muthukumar Karuppasamy
- YaAn Pharmaceutical and Medical Communications, 6/691H1, Balaji Nagar, Sithurajapuram, Sivakasi, 626189, Tamilnadu, India
| | - Biswa Mohan Sahoo
- Roland Institute of Pharmaceutical Sciences, Berhampur, 760010, Odisha, India
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22
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Zhang J, Li S, Dong Y, Tang H, He Y, Hu H, Feng J. Synthesis and biological evaluation of glucagon-like peptide-1 analogs with the C-terminal helix 3 of albumin-binding domain 3. Bioorg Med Chem 2022; 62:116725. [PMID: 35358863 DOI: 10.1016/j.bmc.2022.116725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/07/2022] [Accepted: 03/22/2022] [Indexed: 11/02/2022]
Abstract
Based on peptide 6 (Ser8-GLP-1 [7-35]-GVKALIDEILAA-NH2; GVKALI-DEILAA is the C-terminal helix 3 of albumin-binding domain 3 of protein G from bacterial Streptococcal G strain 148 [G148-ABD3]), a series of its analogs (compounds 0-VI: Aib8-GLP-1 [7-35]-linkers-GVKALIDEILAA-NH2) were designed and synthesized using microwave-assisted solid-phase synthesis. First, to monitor the reaction process and reduce potential risks, the synthesis process of compounds 0-VI was divided into three stages. Next, to explore the effect of these linkers on their albumin-binding rates, albumin-binding assays were performed. Finally, to evaluate their biological activities in vitro and in vivo, receptor potency, surface plasmon resonance (SPR), weight-loss, and glucose-lowering assays were carried out. These results indicated the linkers of different polarities between Aib8-GLP-1 (7-35) and the C-terminal helix 3 of ABD3 can significantly affect the albumin-binding rate of the C-terminal helix 3 of ABD3. And compound IV had the highest albumin-binding rates, weight-loss, and glucose-lowering effects among them.
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Affiliation(s)
- Jinhua Zhang
- China State Institute of Pharmaceutical Industry, Shanghai, China; Department of Biological Medicines & Shanghai Engineering Research Centre of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China
| | - Shanshan Li
- China State Institute of Pharmaceutical Industry, Shanghai, China; Shanghai Duomirui Biotechnology Ltd., Shanghai, China
| | - Yuanzhen Dong
- China State Institute of Pharmaceutical Industry, Shanghai, China; Shanghai Duomirui Biotechnology Ltd., Shanghai, China
| | - Hanqing Tang
- Shanghai Duomirui Biotechnology Ltd., Shanghai, China
| | - Yufeng He
- Shanghai Duomirui Biotechnology Ltd., Shanghai, China
| | - Haifeng Hu
- China State Institute of Pharmaceutical Industry, Shanghai, China.
| | - Jun Feng
- China State Institute of Pharmaceutical Industry, Shanghai, China; Shanghai Duomirui Biotechnology Ltd., Shanghai, China.
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23
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Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes 2022; 13:85-96. [PMID: 35211246 PMCID: PMC8855136 DOI: 10.4239/wjd.v13.i2.85] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/29/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.
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Affiliation(s)
- Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45221, Greece
| | - Michael S Kostapanos
- Lipid Clinic, Department of General Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Athanasia K Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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24
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Gabe MBN, Skov-Jeppesen K, Gasbjerg LS, Schiellerup SP, Martinussen C, Gadgaard S, Boer GA, Oeke J, Torz LJ, Veedfald S, Svane MS, Bojsen-Møller KN, Madsbad S, Holst JJ, Hartmann B, Rosenkilde MM. GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. Pharmacol Res 2022; 176:106058. [PMID: 34995796 DOI: 10.1016/j.phrs.2022.106058] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 01/02/2022] [Accepted: 01/02/2022] [Indexed: 11/22/2022]
Abstract
The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.
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Affiliation(s)
- Maria Buur Nordskov Gabe
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lærke Smidt Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Sine Pasch Schiellerup
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Christoffer Martinussen
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | - Sarina Gadgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Geke Aline Boer
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jannika Oeke
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lola Julia Torz
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Simon Veedfald
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Maria Saur Svane
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Endocrinology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | | | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
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25
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Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. Nat Commun 2022; 13:92. [PMID: 35013280 PMCID: PMC8748714 DOI: 10.1038/s41467-021-27760-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 12/07/2021] [Indexed: 12/31/2022] Open
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists. The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.
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26
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Pechenov S, Revell J, Will S, Naylor J, Tyagi P, Patel C, Liang L, Tseng L, Huang Y, Rosenbaum AI, Balic K, Konkar A, Grimsby J, Subramony JA. Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease. Sci Rep 2021; 11:22521. [PMID: 34795324 PMCID: PMC8602401 DOI: 10.1038/s41598-021-01750-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/01/2021] [Indexed: 01/13/2023] Open
Abstract
Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease. We describe a comprehensive multidisciplinary approach leading to the development of MEDI7219, a GLP-1 receptor agonist (GLP-1RA) specifically engineered for oral delivery. Sites of protease/peptidase vulnerabilities in GLP-1 were removed by amino acid substitution and the peptide backbone was bis-lipidated to promote MEDI7219 reversible plasma protein binding without affecting potency. A combination of sodium chenodeoxycholate and propyl gallate was used to enhance bioavailability of MEDI7219 at the site of maximal gastrointestinal absorption, targeted by enteric-coated tablets. This synergistic approach resulted in MEDI7219 bioavailability of ~ 6% in dogs receiving oral tablets. In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics.
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Affiliation(s)
- Sergei Pechenov
- Drug Delivery, Dosage Form Design and Development, AstraZeneca, Gaithersburg, MD, USA
| | | | - Sarah Will
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Jacqueline Naylor
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Puneet Tyagi
- Drug Delivery, Dosage Form Design and Development, AstraZeneca, Gaithersburg, MD, USA
| | - Chandresh Patel
- Drug Delivery, Dosage Form Design and Development, AstraZeneca, Gaithersburg, MD, USA
| | - Lihuan Liang
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Leo Tseng
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA
| | - Yue Huang
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA
| | - Anton I Rosenbaum
- Integrated Bioanalysis, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, South San Francisco, CA, USA
| | - Kemal Balic
- Integrated Bioanalysis, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, South San Francisco, CA, USA
| | - Anish Konkar
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Joseph Grimsby
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
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27
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Yang Y, Shi J, Zhu J. Diagnostic performance of noninvasive imaging modalities for localization of insulinoma: A meta-analysis. Eur J Radiol 2021; 145:110016. [PMID: 34763145 DOI: 10.1016/j.ejrad.2021.110016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/25/2021] [Accepted: 10/31/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Insulinoma is the most common functional neuroendocrine tumor found only in the pancreas. The early detection of insulinoma is of importance. Studies comparing the performance of noninvasive modalities were limited by sample size and heterogeneity between studies. The aim of this meta-analysis was to evaluate the diagnostic performance of PET/CT, SPECT/CT, CT and MRI for the localization of insulinoma, and to provide evidence for clinical practice. METHODS PubMed, Embase, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure were searched from inception to May 31, 2021. Pooled sensitivity, specificity, positive Likelihood Ratio (+LR) and negative Likelihood Ratio (-LR), diagnostic odds ratio (DOR), and concordance rate were calculated. RESULTS A total of 19 studies including 708 patients of insulinoma reached the inclusion criteria. PET/CT imaging demonstrated a pooled sensitivity of 0.79 (95% CI: 0.54-0.92) and a pooled specificity of 0.84 (95% CI: 0.20-0.99). The pooled sensitivity and specificity of SPECT/CT were 0.77 (95% CI: 0.46-0.93) and 0.45 (95% CI: 0.22-0.70). CT showed an overall sensitivity of 0.54 (95% CI: 0.35-0.72) and specificity of 0.75 (95% CI: 0.54-0.88). The pooled sensitivity and specificity for MRI were 0.54 (95% CI: 0.31-0.75) and 0.65 (95% CI: 0.39-0.84), respectively. The concordance rates of PET, SPECT, CT, and MRI were 78% (95% CI: 66-90%), 74% (95% CI: 52-97%), 56% (95% CI: 41-72%), and 53% (95% CI: 33-73%), respectively. CONCLUSION Results of this study indicate that PET/CT demonstrated superior performance than SPECT/CT, CT and MRI for the localization of insulinoma. GLP-1R based PET/CT manifested better diagnostic performance in comparison with SSTR based PET/CT imaging modality.
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Affiliation(s)
- Yi Yang
- Department of Nuclear Medicine, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, PR China
| | - Jian Shi
- Department of Radiology, Suzhou Integrative Traditional Chinese and Western Medicine Hospital, Suzhou, Jiangsu Province, PR China
| | - Jianbing Zhu
- Department of Radiology, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, PR China.
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28
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Amyloidogenicity of peptides targeting diabetes and obesity. Colloids Surf B Biointerfaces 2021; 209:112157. [PMID: 34715595 DOI: 10.1016/j.colsurfb.2021.112157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 09/20/2021] [Accepted: 10/09/2021] [Indexed: 12/15/2022]
Abstract
Since the discovery of insulin, a century ago, the repertoire of therapeutic polypeptides targeting diabetes - and now also obesity - have increased substantially. The focus on quality has shifted from impure and unstable preparations of animal insulin to highly pure, homologous recombinant insulin, along with other peptide-based hormones and analogs such as amylin analogs (pramlintide, davalintide, cagrilintide), glucagon and glucagon-like peptide-1 receptor agonists (GLP-1, liraglutide, exenatide, semaglutide). Proper formulation, storage, manipulation and usage by professionals and patients are required in order to avoid agglomeration into high molecular weight products (HMWP), either amorphous or amyloid, which could result in potential loss of biological activity and short- or long-term immune reaction and silent inactivation. In this narrative review, we present perspective of the aggregation of therapeutic polypeptides used in diabetes and other metabolic diseases, covering the nature and mechanisms, analytical techniques, physical and chemical stability, strategies aimed to hamper the formation of HMWP, and perspectives on future biopharmaceutical developments.
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29
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Pickford P, Lucey M, Rujan RM, McGlone ER, Bitsi S, Ashford FB, Corrêa IR, Hodson DJ, Tomas A, Deganutti G, Reynolds CA, Owen BM, Tan TM, Minnion J, Jones B, Bloom SR. Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist. Mol Metab 2021; 51:101242. [PMID: 33933675 PMCID: PMC8163982 DOI: 10.1016/j.molmet.2021.101242] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/19/2021] [Accepted: 04/22/2021] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study, we investigated the cellular and metabolic effects of modulating the balance between G protein and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. METHODS Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify the effects on glucose homeostasis and weight loss. RESULTS Ligand-specific reductions in β-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide despite a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. CONCLUSIONS Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.
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Affiliation(s)
- Phil Pickford
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - Maria Lucey
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - Roxana-Maria Rujan
- Centre for Sport, Exercise, and Life Sciences, Faculty of Health and Life Sciences, Coventry University, Alison Gingell Building, CV1 5FB, UK
| | - Emma Rose McGlone
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - Stavroula Bitsi
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - Fiona B Ashford
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | | | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - Giuseppe Deganutti
- Centre for Sport, Exercise, and Life Sciences, Faculty of Health and Life Sciences, Coventry University, Alison Gingell Building, CV1 5FB, UK
| | - Christopher A Reynolds
- Centre for Sport, Exercise, and Life Sciences, Faculty of Health and Life Sciences, Coventry University, Alison Gingell Building, CV1 5FB, UK; School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK
| | - Bryn M Owen
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - Tricia M Tan
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - James Minnion
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
| | - Ben Jones
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK.
| | - Stephen R Bloom
- Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, W12 0NN, UK
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Zhang J, Dong Y, Ju D, Feng J. Design, synthesis and biological evaluation of double fatty chain-modified glucagon-like peptide-1 conjugates. Bioorg Med Chem 2021; 44:116291. [PMID: 34216986 DOI: 10.1016/j.bmc.2021.116291] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/15/2021] [Accepted: 06/20/2021] [Indexed: 10/21/2022]
Abstract
Twelve double fatty chains and Aib8-Arg34-GLP-1 (7-37) were designed and obtained by microwave-assisted solid-phase synthesis. Then, twelve conjugates of Aib8-Arg34-GLP-1 (7-37) were synthesized in 1% triethylamine aqueous solution. Conjugates 2, 3, 6, 7, 10 and 11 showed better GLP-1 receptor activation potency than semaglutide. However, conjugates 2, 6 and 10 showed slightly worse glucose-lowering effects in vivo than semaglutide but better effects than conjugates 3, 7 and 11. The CD spectra of conjugates 2, 6 and 10 indicated that they had the same secondary structure as liraglutide and semaglutide. The receptor affinity results for conjugates 2, 6 and 10 measured by SPR (surface plasmon resonance) showed that conjugate 2 had higher receptor affinity than conjugates 6 and 10. In addition, albumin binding assays indicated that double fatty acid chains had obvious synergistic effects compared with single fatty acid chains. In conclusion, the structure-activity relationship of different side chains was summarized and one candidate, conjugate 2, was screened.
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Affiliation(s)
- Jinhua Zhang
- Department of Biological Medicines & Shanghai Engineering Research Centre of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China; China State Institute of Pharmaceutical Industry, Shanghai, China
| | - Yuanzhen Dong
- China State Institute of Pharmaceutical Industry, Shanghai, China
| | - Dianwen Ju
- Department of Biological Medicines & Shanghai Engineering Research Centre of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China.
| | - Jun Feng
- China State Institute of Pharmaceutical Industry, Shanghai, China; Shanghai Duomirui Biotechnology Ltd., Shanghai, China.
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31
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Novel formulations and drug delivery systems to administer biological solids. Adv Drug Deliv Rev 2021; 172:183-210. [PMID: 33705873 DOI: 10.1016/j.addr.2021.02.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/28/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022]
Abstract
Recent advances in formulation sciences have expanded the previously limited design space for biological modalities, including peptide, protein, and vaccine products. At the same time, the discovery and application of new modalities, such as cellular therapies and gene therapies, have presented formidable challenges to formulation scientists. We explore these challenges and highlight the opportunities to overcome them through the development of novel formulations and drug delivery systems as biological solids. We review the current progress in both industry and academic laboratories, and we provide expert perspectives in those settings. Formulation scientists have made a tremendous effort to accommodate the needs of these novel delivery routes. These include stability-preserving formulations and dehydration processes as well as dosing regimes and dosage forms that improve patient compliance.
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Effect of C-terminus Conjugation via Different Conjugation Chemistries on In Vivo Activity of Albumin-Conjugated Recombinant GLP-1. Pharmaceutics 2021; 13:pharmaceutics13020263. [PMID: 33672039 PMCID: PMC7919490 DOI: 10.3390/pharmaceutics13020263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/12/2021] [Accepted: 02/12/2021] [Indexed: 12/15/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a peptide hormone with tremendous therapeutic potential for treating type 2 diabetes mellitus. However, the short half-life of its native form is a significant drawback. We previously prolonged the plasma half-life of GLP-1 via site-specific conjugation of human serum albumin (HSA) at position 16 of recombinant GLP-1 using site-specific incorporation of p-azido-phenylalanine (AzF) and strain-promoted azide-alkyne cycloaddition (SPAAC). However, the resulting conjugate GLP1_8G16AzF-HSA showed only moderate in vivo glucose-lowering activity, probably due to perturbed interactions with GLP-1 receptor (GLP-1R) caused by the albumin-linker. To identify albumin-conjugated GLP-1 variants with enhanced in vivo glucose-lowering activity, we investigated the conjugation of HSA to a C-terminal region of GLP-1 to reduce steric hindrance by the albumin-linker using two different conjugation chemistries. GLP-1 variants GLP1_8G37AzF-HSA and GLP1_8G37C-HSA were prepared using SPAAC and Michael addition, respectively. GLP1_8G37C-HSA exhibited a higher glucose-lowering activity in vivo than GLP1_8G16AzF-HSA, while GLP1_8G37AzF-HSA did not. Another GLP-1 variant, GLP1_8A37C-HSA, had a glycine to alanine mutation at position 8 and albumin at its C-terminus and exhibited in vivo glucose-lowering activity comparable to that of GLP1_8G37C-HSA, despite a moderately shorter plasma half-life. These results showed that site-specific HSA conjugation to the C-terminus of GLP-1 via Michael addition could be used to generate GLP-1 variants with enhanced glucose-lowering activity and prolonged plasma half-life in vivo.
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Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia. Int J Mol Sci 2021; 22:ijms22020660. [PMID: 33440821 PMCID: PMC7826980 DOI: 10.3390/ijms22020660] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.
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Jia S, Wang Z, Han R, Zhang Z, Li Y, Qin X, Zhao M, Xiang R, Yang J. Incretin mimetics and sodium-glucose co-transporter 2 inhibitors as monotherapy or add-on to metformin for treatment of type 2 diabetes: a systematic review and network meta-analysis. Acta Diabetol 2021; 58:5-18. [PMID: 32514989 DOI: 10.1007/s00592-020-01542-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Although there are many different methods of treating type 2 diabetes (T2D), it is still difficult to draw coincident conclusions concerning the efficacy and safety of different classes of new drugs, and the recommendation level of them has still kept uncertain as second anti-diabetic agents. Therefore, the aim of this study was to summarize evidence on the efficacy and safety of DPP-4is, GLP-1RAs and SGLT-2is as monotherapy or add-on to metformin (Met) for treatment of T2D. MATERIALS AND METHODS We searched PubMed, Embase, Cochrane library and ClinicalTrials.gov for relevant articles in keeping with established methods using terms associated with anti-diabetic agents up to February, 2020, with no start date restriction. Weighted mean difference and risk ratios with 95% confidence intervals were calculated within traditional and network meta-analysis. Primary outcomes were the mean change in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) change and the frequency of hypoglycemic events from baseline after 12 weeks of treatment. RESULTS In total, 64 eligible studies comprising 37,780 patients and 7 treatment strategies were included. The results of primary outcomes showed that GLP-1RAs were significantly more effective than DPP-4is or SGLT-2is in reducing HbA1c when add-on to Met. For FPG, both GLP-1RAs and SGLT-2is significantly reduced FPG compared with DPP-4is whether add-on to Met or not. For hypoglycemia, monotherapy has a lower risk than combination therapy except for SGLT-2is. Ranking probability analysis indicated that GLP-1RAs and SGLT-2is, respectively, reduced HbA1c and FPG most when add-on to Met. Meanwhile, GLP-1RAs took the lowest risk to induce the hypoglycemia, whereas GLP-1RAs plus Met the highest. CONCLUSIONS Both GLP-1RAs and SGLT-2is have their own advantages in efficacy and safety. Monotherapy is beneficial for reducing the risk of hypoglycemia. The recommendation should be a patient-centered approach when selecting treatment choices.
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Affiliation(s)
- Shubing Jia
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zhiying Wang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Ruobing Han
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zinv Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yuping Li
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiaotong Qin
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingyi Zhao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Rongwu Xiang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Jingyu Yang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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Jones B, McGlone ER, Fang Z, Pickford P, Corrêa IR, Oishi A, Jockers R, Inoue A, Kumar S, Görlitz F, Dunsby C, French PMW, Rutter GA, Tan T, Tomas A, Bloom SR. Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signaling at glucagon family receptors. J Biol Chem 2021; 296:100133. [PMID: 33268378 PMCID: PMC7948418 DOI: 10.1074/jbc.ra120.016334] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 01/20/2023] Open
Abstract
Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.
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Affiliation(s)
- Ben Jones
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom.
| | - Emma Rose McGlone
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
| | - Zijian Fang
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
| | - Phil Pickford
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
| | | | - Atsuro Oishi
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Ralf Jockers
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Sunil Kumar
- Department of Physics, Imperial College London, London, United Kingdom
| | - Frederik Görlitz
- Department of Physics, Imperial College London, London, United Kingdom
| | - Chris Dunsby
- Department of Physics, Imperial College London, London, United Kingdom
| | - Paul M W French
- Department of Physics, Imperial College London, London, United Kingdom
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Tricia Tan
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom.
| | - Stephen R Bloom
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
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Chen X, Fu J, Zhou F, Yang Q, Wang J, Feng H, Jiang W, Jin L, Tang X, Jiang N, Yin J, Han J. Stapled and Xenopus Glucagon-Like Peptide 1 (GLP-1)-Based Dual GLP-1/Gastrin Receptor Agonists with Improved Metabolic Benefits in Rodent Models of Obesity and Diabetes. J Med Chem 2020; 63:12595-12613. [PMID: 33125843 DOI: 10.1021/acs.jmedchem.0c00736] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Diabetes is characterized by pancreas dysfunction and is commonly associated with obesity. Hypoglycemic agents capable of improving β-cell function and reducing body weight therefore are gaining increasing interest. Though glucagon-like peptide 1 receptor (GLP-1R)/cholecystokinin 2 receptor (CCK-2R) dual agonist ZP3022 potently increases β-cell mass and improves glycemic control in diabetic db/db mice, the in vivo half-life (t1/2) is short, and its body weight reducing activity is limited. Here, we report the discovery of a series of novel GLP-1R/CCK-2R dual agonists. Starting from Xenopus GLP-1, dual cysteine mutation was conducted followed by covalent side chain stapling and albumin binder incorporation, resulting in a stabilized secondary structure, increased agonist potency, and improved stability. Further C-terminal conjugation of gastrin-6 generated GLP-1R/CCK-2R dual agonists, among which 6a and 6b showed higher stability and hypoglycemic activity than liraglutide and ZP3022. Desirably, 6a and 6b exhibited prominent metabolic benefits in diet-induced obesity mice without causing nausea responses and exerted considerable effects on β-cell restoration in db/db mice. These preclinical studies suggest the potential role of GLP-1R/CCK-2R dual agonists as effective agents for treating diabetes and related metabolic disorders.
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Affiliation(s)
- Xinyu Chen
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Junjie Fu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, PR China
| | - Feng Zhou
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Qimeng Yang
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Jialing Wang
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Hui Feng
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Wen Jiang
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Luofan Jin
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Xuelin Tang
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China
| | - Neng Jiang
- Department of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, PR China
| | - Jian Yin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, PR China
| | - Jing Han
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China.,Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, PR China
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Pickford P, Lucey M, Fang Z, Bitsi S, de la Serna JB, Broichhagen J, Hodson DJ, Minnion J, Rutter GA, Bloom SR, Tomas A, Jones B. Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide. Br J Pharmacol 2020; 177:3905-3923. [PMID: 32436216 PMCID: PMC7429481 DOI: 10.1111/bph.15134] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 04/22/2020] [Accepted: 04/28/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND AND PURPOSE Amino acid substitutions at the N-termini of glucagon-like peptide-1 (GLP-1) receptor agonist peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here, we to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1 receptor agonists exendin-4 and lixisenatide lead to similar phenomena. EXPERIMENTAL APPROACH Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time-resolved FRET approaches were developed to study agonist behaviours at the cellular and sub-cellular level. Anti-hyperglycaemic and anorectic effects of each parent ligand and their biased derivatives were assessed in mice. KEY RESULTS Lixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was fivefold less potent for cAMP signalling. Both peptides induced extensive GLP-1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1 receptor recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide. N-terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose. CONCLUSION AND IMPLICATIONS Changes to the C-terminus of exendin-4 affect signalling potency and GLP-1 receptor trafficking via mechanisms unrelated to GLP-1 receptor occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.
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Affiliation(s)
- Philip Pickford
- Section of Endocrinology and Investigative MedicineImperial College LondonLondonUK
| | - Maria Lucey
- Section of Endocrinology and Investigative MedicineImperial College LondonLondonUK
| | - Zijian Fang
- Section of Endocrinology and Investigative MedicineImperial College LondonLondonUK
| | - Stavroula Bitsi
- Section of Cell Biology and Functional GenomicsImperial College LondonLondonUK
| | | | - Johannes Broichhagen
- Department Chemical BiologyMax Planck Institute for Medical ResearchHeidelbergGermany
- Department Chemical BiologyLeibniz‐Forschungsinstitut für Molekulare Pharmakologie (FMP)BerlinGermany
| | - David J. Hodson
- Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE)University of BirminghamBirminghamUK
- Centre for Endocrinology, Diabetes and MetabolismBirmingham Health PartnersBirminghamUK
| | - James Minnion
- Section of Endocrinology and Investigative MedicineImperial College LondonLondonUK
| | - Guy A. Rutter
- Section of Cell Biology and Functional GenomicsImperial College LondonLondonUK
| | - Stephen R. Bloom
- Section of Endocrinology and Investigative MedicineImperial College LondonLondonUK
| | - Alejandra Tomas
- Section of Cell Biology and Functional GenomicsImperial College LondonLondonUK
| | - Ben Jones
- Section of Endocrinology and Investigative MedicineImperial College LondonLondonUK
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Cao C, Wei S, Xu X, Song S, Lai Y, Li J. Signal Peptide Optimization to Prevent N-terminal Truncation of Glucagon Like Peptide-1/IgG-Fc Fusion Protein. Int J Pept Res Ther 2020. [DOI: 10.1007/s10989-020-10112-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Bird GH, Fu A, Escudero S, Godes M, Opoku-Nsiah K, Wales TE, Cameron MD, Engen JR, Danial NN, Walensky LD. Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor. ACS Chem Biol 2020; 15:1340-1348. [PMID: 32348108 DOI: 10.1021/acschembio.0c00308] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Glucagon-like peptide 1 (GLP-1) is a natural peptide agonist of the GLP-1 receptor (GLP-1R) found on pancreatic β-cells. Engagement of the receptor stimulates insulin release in a glucose-dependent fashion and increases β-cell mass, two ideal features for pharmacologic management of type 2 diabetes. Thus, intensive efforts have focused on developing GLP-1-based peptide agonists of GLP-1R for therapeutic application. A primary challenge has been the naturally short half-life of GLP-1 due to its rapid proteolytic degradation in vivo. Whereas mutagenesis and lipidation strategies have yielded clinical agents, we developed an alternative approach to preserving the structure and function of GLP-1 by all-hydrocarbon i, i + 7 stitching. This particular "stitch" is especially well-suited for reinforcing and protecting the structural fidelity of GLP-1. Lead constructs demonstrate striking proteolytic stability and potent biological activity in vivo. Thus, we report a facile approach to generating alternative GLP-1R agonists for glycemic control.
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Affiliation(s)
- Gregory H. Bird
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
- Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
| | - Accalia Fu
- Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston Massachusetts 02215, United States
- Department of Cell Biology, Harvard Medical School, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, United States
| | - Silvia Escudero
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
- Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
| | - Marina Godes
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
- Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
| | - Kwadwo Opoku-Nsiah
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
- Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
| | - Thomas E. Wales
- Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States
| | - Michael D. Cameron
- DMPK Core, Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - John R. Engen
- Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States
| | - Nika N. Danial
- Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston Massachusetts 02215, United States
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
- Department of Medicine, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, United States
| | - Loren D. Walensky
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
- Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, United States
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Alavi SE, Cabot PJ, Yap GY, Moyle PM. Optimized Methods for the Production and Bioconjugation of Site-Specific, Alkyne-Modified Glucagon-like Peptide-1 (GLP-1) Analogs to Azide-Modified Delivery Platforms Using Copper-Catalyzed Alkyne–Azide Cycloaddition. Bioconjug Chem 2020; 31:1820-1834. [DOI: 10.1021/acs.bioconjchem.0c00291] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Seyed Ebrahim Alavi
- School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Queensland 4102, Australia
| | - Peter John Cabot
- School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Queensland 4102, Australia
| | - Gee Yi Yap
- School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Queensland 4102, Australia
| | - Peter Michael Moyle
- School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Queensland 4102, Australia
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Jansen TJP, van Lith SAM, Boss M, Brom M, Joosten L, Béhé M, Buitinga M, Gotthardt M. Exendin-4 analogs in insulinoma theranostics. J Labelled Comp Radiopharm 2020; 62:656-672. [PMID: 31070270 PMCID: PMC6771680 DOI: 10.1002/jlcr.3750] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 04/24/2019] [Accepted: 05/03/2019] [Indexed: 12/17/2022]
Abstract
Insulinomas, neuroendocrine tumors arising from pancreatic beta cells, often show overexpression of the glucagon‐like peptide‐1 receptor. Therefore, imaging with glucagon‐like peptide analog exendin‐4 can be used for diagnosis and preoperative localization. This review presents an overview of the development and clinical implementation of exendin‐based tracers for nuclear imaging, and the potential use of exendin‐4 based tracers for optical imaging and therapeutic applications such as peptide receptor radionuclide therapy or targeted photodynamic therapy.
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Affiliation(s)
- Tom J P Jansen
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Sanne A M van Lith
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Marti Boss
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Maarten Brom
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Lieke Joosten
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Martin Béhé
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland
| | - Mijke Buitinga
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands.,Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Martin Gotthardt
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
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Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide. Pharmaceutics 2020; 12:pharmaceutics12040364. [PMID: 32316169 PMCID: PMC7238188 DOI: 10.3390/pharmaceutics12040364] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/10/2020] [Accepted: 04/14/2020] [Indexed: 12/13/2022] Open
Abstract
The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A “clickable” non-natural amino acid—p-azido-l-phenylalanine (AzF)—was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide–alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives.
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43
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Deacon CF. Metabolism of GIP and the contribution of GIP to the glucose-lowering properties of DPP-4 inhibitors. Peptides 2020; 125:170196. [PMID: 31706956 DOI: 10.1016/j.peptides.2019.170196] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 01/26/2023]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with insulinotropic and glucagonotropic actions, and is believed to be the more physiologically important incretin hormone in healthy humans. Together with the other incretin hormone, glucagon-like peptide-1 (GLP-1), it plays an important role in regulating glucose homeostasis. Both GLP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4 (DPP-4), and DPP-4 inhibitors, which potentiate their effects on glycaemic control, are now used to treat type 2 diabetes (T2D). This review describes how post-translational processing of the GIP precursor molecule and post-release degradation of the secretory products give rise to multiple isoforms of GIP, some, but not all of which are biologically active, and discusses how this impacts upon their measurement by immunological- and bioassay-based methods. DPP-4 inhibitors reduce degradation of GIP, and although the insulinotropic effects of GIP are impaired in patients with T2D, they can be at least partially restored if glycaemic control is improved. Therefore, given that studies with incretin receptor antagonists indicate that not all of the glucose-lowering effects of DPP-4 inhibition can be accounted for by GLP-1 alone, evidence supports the notion that GIP may play a role in mediating the anti-hyperglycaemic effects of DPP-4 inhibition, while its glucagonotropic actions at lower glucose levels may contribute to the low risk of hypoglycaemia associated with DPP-4 inhibitors.
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Affiliation(s)
- Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
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Abstract
PURPOSE OF REVIEW Among the gastrointestinal hormones, the incretins: glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 have attracted interest because of their importance for the development and therapy of type 2 diabetes and obesity. New agonists and formulations of particularly the GLP-1 receptor have been developed recently showing great therapeutic efficacy for both diseases. RECENT FINDINGS The status of the currently available GLP-1 receptor agonists (GLP-1RAs) is described, and their strengths and weaknesses analyzed. Their ability to also reduce cardiovascular and renal risk is described and analysed. The most recent development of orally available agonists and of very potent monomolecular co-agonists for both the GLP-1 and GIP receptor is also discussed. SUMMARY The GLP-1RAs are currently the most efficacious agents for weight loss, and show potential for further efficacy in combination with other food-intake-regulating peptides. Because of their glycemic efficacy and cardiorenal protection, the GLP-1 RAs will be prominent elements in future diabetes therapy.
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Affiliation(s)
- Jens Juul Holst
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, Denmark
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45
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Song X, Yu Y, Shen C, Wang Y, Wang N. Dimerization/oligomerization of the extracellular domain of the GLP-1 receptor and the negative cooperativity in its ligand binding revealed by the improved NanoBiT. FASEB J 2020; 34:4348-4368. [PMID: 31970836 DOI: 10.1096/fj.201902007r] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 12/15/2019] [Accepted: 01/12/2020] [Indexed: 12/13/2022]
Abstract
The glucagon-like peptide-1 receptor (GLP-1R), a family B G-protein coupled receptor (GPCR), regulates the insulin secretion following stimulation by ligands. The transmembrane domain (TM) mediates GLP-1R homodimerization, which modulates its ligand binding and signaling. We investigated the possible involvement of the N-terminal extracellular domain (NTD) in dimerization/oligomerization and dimer-associated ligand binding by NanoLuc Binary Technology (NanoBiT). With improved NanoBiT detection using a decreasing substrate concentration, the negative cooperativity of ligand binding to the NTD was confirmed by accelerated dissociation and Scatchard analysis. The dimerization/oligomerization of the isolated NTD was observed by NanoBiT and validated by analytical ultracentrifugation, deriving the comparable dimerization affinity (~105 M-1 ). The NTD was also involved in the dimerization/oligomerization of the full-length GLP-1R with mutated TM4 at the cellular level. In an analysis of the parameters of the NTD binding, the Kd for the probe GLP-1 (7-36, A8G) was similar (6-8 μM) in both the 1:1 binding model and the receptor dimerization model. Compared with GLP-1 and dulaglutide, exenatide showed two-site binding with Ki values of 1.4 pM and 8.7 nM. Our study indicates the involvement of NTD in the GLP-1R dimerization/oligomerization and suggests that further investigations on the role in other family B GPCRs are needed.
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Affiliation(s)
- Xiaohan Song
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Yi Yu
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Cangjie Shen
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Yubo Wang
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Nan Wang
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
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Grandl G, Novikoff A, DiMarchi R, Tschöp MH, Müller TD. Gut Peptide Agonism in the Treatment of Obesity and Diabetes. Compr Physiol 2019; 10:99-124. [PMID: 31853954 DOI: 10.1002/cphy.c180044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism. © 2020 American Physiological Society. Compr Physiol 10:99-124, 2020.
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Affiliation(s)
- Gerald Grandl
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Richard DiMarchi
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany.,Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany
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Sannikova EP, Bulushova NV, Cheperegin SE, Zalunin IA, Klebanov FA, Gracheva TS, Yurin VL, Rykalina NV, Askerova EV, Yarotskii SV, Tatarnikova OG, Bobkova NV, Kozlov DG. Specific Activity of Recombinant Modified Human Glucagon-Like Peptide 1. APPL BIOCHEM MICRO+ 2019. [DOI: 10.1134/s0003683819070068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Cary BP, Hager MV, Gellman SH. Impact of Substitution Registry on the Receptor-Activation Profiles of Backbone-Modified Glucagon-like Peptide-1 Analogues. Chembiochem 2019; 20:2834-2840. [PMID: 31172641 PMCID: PMC6861653 DOI: 10.1002/cbic.201900300] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Indexed: 12/20/2022]
Abstract
Family B G protein-coupled receptors play important physiological roles and possess large extracellular domains (ECDs) that aid in binding the long polypeptide hormones that are their natural agonists. We have previously shown that agonist analogues in which subsets of native α-amino acid residues are replaced with β-amino acid residues can retain activity while avoiding proteolytic degradation. This study focuses on eight new α/β analogues of glucagon-like peptide 1 (GLP-1) that each contain five α-to-β replacements in the C-terminal half of the peptide. This portion of GLP-1 is known to adopt an α-helical conformation and contact the ECD. All four registries of the αααβ backbone pattern were evaluated; previous work has shown that the αααβ pattern supports adoption of an α-helix-like conformation. Two α-to-β replacement formats were employed, one involving β3 homologues of the native residues replaced and the other involving a cyclic β residue. GLP-1R response was characterized in terms of stimulation of cAMP production and β-arrestin recruitment. Some of the backbone-modified GLP-1 analogues display biased agonism of the GLP-1R. This study helps to establish the scope of the α→β backbone modification strategy.
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Affiliation(s)
- Brian P. Cary
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706 United States
| | - Marlies V. Hager
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706 United States
| | - Samuel H. Gellman
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706 United States
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49
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Novel lipid side chain modified exenatide analogs emerged prolonged glucoregulatory activity and potential body weight management properties. Bioorg Med Chem 2019; 27:115070. [DOI: 10.1016/j.bmc.2019.115070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 11/22/2022]
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50
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Levine PM, Balana AT, Sturchler E, Koole C, Noda H, Zarzycka B, Daley EJ, Truong TT, Katritch V, Gardella TJ, Wootten D, Sexton PM, McDonald P, Pratt MR. O-GlcNAc Engineering of GPCR Peptide-Agonists Improves Their Stability and in Vivo Activity. J Am Chem Soc 2019; 141:14210-14219. [PMID: 31418572 PMCID: PMC6860926 DOI: 10.1021/jacs.9b05365] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Peptide agonists of GPCRs and other receptors are powerful signaling molecules with high potential as biological tools and therapeutics, but they are typically plagued by instability and short half-lives in vivo. Nature uses protein glycosylation to increase the serum stability of secreted proteins. However, these extracellular modifications are complex and heterogeneous in structure, making them an impractical solution. In contrast, intracellular proteins are subjected to a simple version of glycosylation termed O-GlcNAc modification. In our studies of this modification, we found that O-GlcNAcylation inhibits proteolysis, and strikingly, this stabilization occurs despite large distances in primary sequence (10-15 amino acids) between the O-GlcNAc and the site of cleavage. We therefore hypothesized that this "remote stabilization" concept could be useful to engineer the stability and potentially additional properties of peptide or protein therapeutics. Here, we describe the application of O-GlcNAcylation to two clinically important peptides: glucagon-like peptide-1 (GLP-1) and the parathyroid hormone (PTH), which respectively help control glucose and calcium levels in the blood. For both peptides, we found O-GlcNAcylated analogs that are equipotent to unmodified peptide in cell-based activation assays, while several GLP-1 analogs were biased agonists relative to GLP-1. As we predicted, O-GlcNAcylation can improve the stability of both GLP-1 and PTH in serum despite the fact that the O-GlcNAc can be quite remote from characterized sites of peptide cleavage. The O-GlcNAcylated GLP-1 and PTH also displayed significantly improved in vivo activity. Finally, we employed structure-based molecular modeling and receptor mutagenesis to predict how O-GlcNAcylation can be accommodated by the receptors and the potential interactions that contribute to peptide activity. This approach demonstrates the potential of O-GlcNAcylation for generating analogs of therapeutic peptides with enhanced proteolytic stability.
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Affiliation(s)
| | | | - Emmanuel Sturchler
- Department of Molecular Medicine The Scripps Research Institute , Jupiter , Florida 33458 , United States
| | - Cassandra Koole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology , Monash University , Parkville , VIC 3052 , Australia
| | - Hiroshi Noda
- Endocrine Unit , Massachusetts General Hospital, and Harvard Medical School , Boston , Massachusetts 02114 , United States
| | | | - Eileen J Daley
- Endocrine Unit , Massachusetts General Hospital, and Harvard Medical School , Boston , Massachusetts 02114 , United States
| | - Tin T Truong
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology , Monash University , Parkville , VIC 3052 , Australia
| | - Vsevolod Katritch
- Bridge Institute , University of Southern California , Los Angeles , California 90089 , United States
| | - Thomas J Gardella
- Endocrine Unit , Massachusetts General Hospital, and Harvard Medical School , Boston , Massachusetts 02114 , United States
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology , Monash University , Parkville , VIC 3052 , Australia
| | - Patrick M Sexton
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology , Monash University , Parkville , VIC 3052 , Australia
| | - Patricia McDonald
- Department of Molecular Medicine The Scripps Research Institute , Jupiter , Florida 33458 , United States
| | - Matthew R Pratt
- Bridge Institute , University of Southern California , Los Angeles , California 90089 , United States
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