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Uversky VN. How to drug a cloud? Targeting intrinsically disordered proteins. Pharmacol Rev 2024; 77:PHARMREV-AR-2023-001113. [PMID: 39433443 DOI: 10.1124/pharmrev.124.001113] [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: 06/16/2024] [Revised: 10/03/2024] [Accepted: 10/15/2024] [Indexed: 10/23/2024] Open
Abstract
Biologically active proteins/regions without stable structure (i.e., intrinsically disordered proteins and regions (IDPs and IDRs)) are commonly found in all proteomes. They have a unique functional repertoire that complements the functionalities of ordered proteins and domains. IDPs/IDRs are multifunctional promiscuous binders capable of folding at interaction with specific binding partners on a template- or context-dependent manner, many of which undergo liquid-liquid phase separation, leading to the formation of membrane-less organelles and biomolecular condensates. Many of them are frequently related to the pathogenesis of various human diseases. All this defines IDPs/IDRs as attractive targets for the development of novel drugs. However, their lack of unique structures, multifunctionality, binding promiscuity, and involvement in unusual modes of action preclude direct use of traditional structure-based drug design approaches for targeting IDPs/IDRs, and make disorder-based drug discovery for these "protein clouds" challenging. Despite all these complexities there is continuing progress in the design of small molecules affecting IDPs/IDRs. This article describes the major structural features of IDPs/IDRs and the peculiarities of the disorder-based functionality. It also discusses the roles of IDPs/IDRs in various pathologies, and shows why the approaches elaborated for finding drugs targeting ordered proteins cannot be directly used for the intrinsic disorder-based drug design, and introduces some novel methodologies suitable for these purposes. Finally, it emphasizes that regardless of their multifunctionality, binding promiscuity, lack of unique structures, and highly dynamic nature, "protein clouds" are principally druggable. Significance Statement Intrinsically disordered proteins and regions are highly abundant in nature, have multiple important biological functions, are commonly involved in the pathogenesis of a multitude of human diseases, and are therefore considered as very attractive drug targets. Although dealing with these unstructured multifunctional protein/regions is a challenging task, multiple innovative approaches have been designed to target them by small molecules.
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El-Baky NA, Uversky VN, Redwan EM. Human consensus interferons: Bridging the natural and artificial cytokines with intrinsic disorder. Cytokine Growth Factor Rev 2015; 26:637-45. [DOI: 10.1016/j.cytogfr.2015.07.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 07/01/2015] [Accepted: 07/02/2015] [Indexed: 12/13/2022]
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Peciak K, Tommasi R, Choi JW, Brocchini S, Laurine E. Expression of soluble and active interferon consensus in SUMO fusion expression system in E. coli. Protein Expr Purif 2014; 99:18-26. [PMID: 24680730 DOI: 10.1016/j.pep.2014.03.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 03/15/2014] [Accepted: 03/17/2014] [Indexed: 12/24/2022]
Abstract
Protein production can be improved if methods for soluble protein expression are developed. Interferon consensus (IFN-con) is used to treat hepatitis C. IFN-con has superior activity compared to other clinically used interferon α subtypes. However IFN-con is a challenging protein to produce in a soluble form using an Escherichia coli expression system. Here we describe the expression of soluble and active recombinant IFN-con in E. coli. The IFN-con gene sequence was optimised for expression in E. coli, which was then cloned into the Champion™ pET SUMO expression vector downstream of the SUMO fusion protein and under strong T7lac promoter. The SUMO-IFN-con fusion protein was efficiently expressed using the SHuffle™ E. coli strain and existed in soluble form as 86-88% of the total IFN-con. After removal of the SUMO fusion partner, approximately 50mg of recombinant IFN-con of at least 98% purity (by RP-HPLC) was obtained from a 1L fermentation culture. Using an A549/EMCV antiviral assay, the specific activity of the recombinant IFN-con was determined to be 960×10(6) IU/mg as calculated to NIBSC standard for IFN-con (3×10(5)pfu/mL virus titre). Comparison of the antiviral activity of the produced IFN-con to IFN α-2a showed that IFN-con displays 2.8 times greater activity, which is in good agreement with what has been reported in the literature for pure protein. IFN-con expression in a soluble form from E. coli allowed us to use a simple, two-step purification process to yield highly pure and active IFN-con which is more efficient than obtaining IFN-con from inclusion bodies.
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Affiliation(s)
- Karolina Peciak
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK; PolyTherics Ltd., The London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
| | - Rita Tommasi
- PolyTherics Ltd., The London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
| | - Ji-won Choi
- PolyTherics Ltd., The London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
| | - Steve Brocchini
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK; PolyTherics Ltd., The London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
| | - Emmanuelle Laurine
- PolyTherics Ltd., The London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK.
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Alao H, Jake Liang T. Alternative interferons and immunomodulators in the treatment of hepatitis C. Liver Int 2014; 34 Suppl 1:133-8. [PMID: 24373090 DOI: 10.1111/liv.12402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Interferon-α (IFN-α) has been the mainstay of therapy for hepatitis C and is currently being combined with other drugs to improve the response rate. Newer therapeutic regimens are being developed to spare the use of IFN because of the important side effects associated with IFN-based therapy. However, there may still be a need for the use of IFN in certain populations. In addition, agents that mimic the actions of IFN but with fewer side effects may still be of major value. This review focuses on the development of alternative and new forms of IFNs and other immunomodulatory agents that may supplant IFN-α in combination therapy for hepatitis C.
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Affiliation(s)
- Hawwa Alao
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Wang BX, Fish EN. The yin and yang of viruses and interferons. Trends Immunol 2012; 33:190-7. [PMID: 22321608 PMCID: PMC7106503 DOI: 10.1016/j.it.2012.01.004] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 12/21/2011] [Accepted: 01/04/2012] [Indexed: 12/15/2022]
Abstract
Interferons (IFNs)-α/β are critical effectors of the innate immune response to virus infections. Through activation of the IFN-α/β receptor (IFNAR), they induce expression of IFN-stimulated genes (ISGs) that encode antiviral proteins capable of suppressing viral replication and promoting viral clearance. Many highly pathogenic viruses have evolved mechanisms to evade an IFN response and the balance between the robustness of the host immune response and viral antagonistic mechanisms determines whether or not the virus is cleared. Here, we discuss IFNs as broad-spectrum antivirals for treatment of acute virus infections. In particular, they are useful for treatment of re-emerging virus infections, where direct-acting antivirals (DAAs) have limited utility due to DAA-resistant mutations, and for newly emerging virus strains in which the time to vaccine availability precludes vaccination at the onset of an outbreak.
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Affiliation(s)
- Ben X Wang
- University Health Network, Toronto, Ontario, Canada
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Cai Y, Zhang Z, Fan K, Zhang J, Shen W, Li M, Si D, Luo H, Zeng Y, Fu P, Liu C. Pharmacokinetics, tissue distribution, excretion, and antiviral activity of pegylated recombinant human consensus interferon-α variant in monkeys, rats and guinea pigs. ACTA ACUST UNITED AC 2011; 173:74-81. [PMID: 21985916 DOI: 10.1016/j.regpep.2011.09.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 08/28/2011] [Accepted: 09/16/2011] [Indexed: 11/25/2022]
Abstract
The study aims to characterize the pharmacokinetic, tissue distribution, excretion, and antiviral activity properties of a novel pegylated recombinant human consensus interferon-α variant (PEG-IFN-SA) following a single subcutaneous administration to monkeys, rats and guinea pigs. Studies included: (1) pharmacokinetic properties of PEG-IFN-SA and comparison with those of non-pegylated IFN-SA in rhesus monkeys and rats; (2) tissue distribution and urinary, fecal, and biliary excretion patterns of (125)I-PEG-IFN-SA in guinea pigs; and (3) antiviral activity assessment of PEG-IFN-SA in cynomolgus monkeys. The pegylated protein exhibited improved pharmacokinetic properties compared to IFN-SA in both monkeys and rats, with a 12-fold and 15-fold increase in elimination half-life, and a 100-fold and 10-fold decrease in serum clearance, as well as a 2.5-fold and 10-fold increase in the time to reach peak serum concentration, respectively. (125)I-PEG-IFN-SA was found to be distributed to most of the tissues examined and has character of targeting special distribution, and urinary appeared to be a major route for the excretion of PEG-IFN-SA in guinea pigs. Serum sample analysis from PEG-IFN-SA-treated monkeys showed dose-dependent antiviral activity for one week. These findings demonstrate that pegylation of IFN-SA results in more desirable pharmacokinetic properties, enhanced drug exposure and sustained-efficacy of in vivo antiviral action.
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Affiliation(s)
- Yongming Cai
- Department of Pharmaceutical Engineering, School of Chemical and Technology, Tianjin University, 92 Weijin Road, Tianjin 300072, China
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Consensus interferon used to treat prior partial-responders to pegylated interferon plus ribavirin. Dig Dis Sci 2011; 56:3032-7. [PMID: 21879283 DOI: 10.1007/s10620-011-1869-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 08/12/2011] [Indexed: 01/08/2023]
Abstract
BACKGROUND The response to pegylated interferon (peg-IFN) plus ribavirin therapy remains less than ideal with 40-50% of treated subjects failing to clear the virus. Moreover, retreatment is only minimally effective. Consensus interferon (c-IFN) has been shown to be efficacious in HCV genotype 1 patients who have failed therapy with peg-IFN. AIM To evaluated the response to re-treatment of peg-IFN plus ribavirin partial-responders with c-IFN plus ribavirin. METHODS Forty-two subjects who had previously failed to clear virus after treatment with peg-IFN plus ribavirin were treated with c-IFN (15 μg/day) plus ribavirin (800-1,200 mg/day) until 12 months of therapy or a total of six consecutive months of PCR negativity was achieved. RESULTS The study population consisted predominantly of males (71%), Caucasians (76%), with African Americans comprising the remaining 24%, subjects with HCV genotype 1 infection (81%) and 21% had cirrhosis by liver biopsy. The overall SVR rate was 29%. The only pretreatment variable that distinguished responders from partial-responders was the serum triglyceride level. CONCLUSIONS The use of c-IFN plus ribavirin in the retreatment of prior peg-IFN plus ribavirin partial responders is essentially twice that achieved in prior re-treatment regimens consisting of a second course of peg-IFN plus ribavirin. These results will need to be evaluated against the use of triple therapy consisting of a peg-IFN plus ribavirin and a protease inhibitor. More studies utilizing c-IFN plus ribavirin with either a protease inhibitor or polymerase inhibitor need to be performed as well.
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Abstract
Consensus interferon (CIFN) is an artificially engineered interferon that reflects most of the human genotype 1 interferons and shows a higher biological and antiviral capacity in vitro. It has been used internationally to treat patients with chronic hepatitis C (HCV) infection before pegylated IFN became available. To mimic the half-life of PEG-IFN it has to be administered on a daily basis. The gold standard in the treatment of hepatitis C is well established and recommended. Today patients are being treated with a combination therapy of pegylated IFN and ribavirin. Length and dosage of therapy depends on the genotype of the virus. Patients with genotype 1 and 4 and high viral load should be treated for 48 weeks; for patients with these genotypes along with either low viral load or early virological response, therapy for 24 weeks is sufficient. Patients with genotype 2 and 3 should be treated for up to 24 weeks. However, daily dosing of IFN-α, eg, CIFN, resulting in a higher cumulative dosage, might be beneficial and more efficacious in some chronic HCV-infected patients. Patients with genotype 1, having initially high viral load (>800,000 IU/mL) and showing advanced liver disease with progressive fibrosis or even cirrhosis comprise the difficult-to-treat in order to overcome the infection. This review summarizes and critically discusses the published data on the treatment of HCV with CIFN.
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Affiliation(s)
- Th Witthöft
- University Hospital Schleswig Holstein, Campus Lübeck, Dept of Medicine I, Division of Gastroenterology, Lübeck, Germany
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Iwasaki Y, Tanaka H, Ikeada H, Okamoto RI, Araki Y, Yabushita K, Kobashi H, Kariyama K, Kawaguchi M, Takaguchi K, Sakata T, Ando M, Sakaguchi K, Aoki N, Shiratori Y. Efficacy and cost-effectiveness of consensus interferon monotherapy with high-dose induction for hepatitis C patients with genotype 2. Scand J Gastroenterol 2011; 46:79-90. [PMID: 20822376 DOI: 10.3109/00365521.2010.516449] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Several treatment strategies for patients with chronic hepatitis C have been compared mainly in terms of their efficacy, and it has been found that pegylated interferon (IFN) plus ribavirin has become the standard therapy, but aged patients may not tolerate ribavirin and the cost-effectiveness of treatment should also be further considered. We conducted a study to evaluate the efficacy, safety, and cost-effectiveness of consensus IFN monotherapy with high-dose induction for patients with chronic hepatitis C in clinical practice. MATERIAL AND METHODS We consecutively enrolled 104 patients with chronic hepatitis C. Patients were scheduled to receive 12 or 18 μg of consensus IFN daily for 2 weeks, then three times a week for 22 weeks. Efficacy, safety, and cost-effectiveness were assessed. A Markov model was developed to investigate cost-effectiveness in patients with chronic hepatitis C treated by different IFN-based treatment strategies. RESULTS Of the 104 study patients, a sustained virological response (SVR) was achieved in 66 (63%). Logistic regression analysis revealed that genotype 2, lower hepatitis C virus RNA levels, and patient age were independently associated with SVR. The response rate was significantly higher in patients with genotype 2 (51/66, 77%) versus genotype 1 (15/38, 40%). Cost-effectiveness analysis in patients with genotype 2 revealed that high-dose induction with consensus IFN monotherapy was as highly cost-effective as pegylated IFN plus ribavirin. CONCLUSION Consensus IFN monotherapy with high-dose induction shows high efficacy and cost-effectiveness in chronic hepatitis C patients with genotype 2 infection. Thus, it may be a reliable alternative in aged patients and for those excluded from standard combination therapy.
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Affiliation(s)
- Yoshiaki Iwasaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
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Retreatment of patients nonresponsive to pegylated interferon and ribavirin with daily high-dose consensus interferon. HEPATITIS RESEARCH AND TREATMENT 2010; 2010:537827. [PMID: 21188197 PMCID: PMC3003973 DOI: 10.1155/2010/537827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Revised: 07/21/2010] [Accepted: 08/04/2010] [Indexed: 11/18/2022]
Abstract
Background. Current treatment of chronic hepatitis C with pegylated interferon and ribavirin has the ability to eliminate viral infection in about half of the patients treated. Therapeutic options, for those with remaining chronic hepatitis, will remain limited until novel antivirals become available in the future. Consensus interferon is currently available and has demonstrated clinical efficacy with superior invitro antiviral activity, but the maximum tolerated dose is not defined. Methods. We assessed the efficacy of daily high-dose (24 ug) consensus interferon with weight-based (1000-1200 mg daily) ribavirin in HCV genotype 1-infected non-responder patients. Results. Six adverse events were documented in five patients, and the trial was terminated with no subject achieving viral clearance. Conclusions. The occurrence of serious adverse events effectively defined the upper limit of acceptable dose, while also revealing that this dose did not offer enhanced sustained viral clearance.
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Comparative efficacy and overall safety of different doses of consensus interferon for treatment of chronic HCV infection: a systematic review and meta-analysis. Eur J Clin Pharmacol 2010; 66:1071-9. [PMID: 20857094 DOI: 10.1007/s00228-010-0881-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Accepted: 07/29/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND About one-half of patients with hepatitis C genotype 1 and one-third with genotype 2/3 have treatment failure with peginterferon alpha and ribavirin. Consensus interferon (CIFN) is an option for retreatment of these patients. OBJECTIVE To summarize comparative safety and efficacy of different regimens of CIFN for the treatment of patients with chronic hepatitis C infection. DATA SOURCE Medline, Scopus, ISI, and Cochran Central Register of Clinical Trials were used. STUDY ELIGIBILITY CRITERIA Randomized clinical trials (RCTs) were eligible for inclusion in the study. PARTICIPANTS HIV and HBV seronegative patients with positive HCV-RNA during the 6 months before the start of the study were eligible for inclusion. INTERVENTIONS Different regimens of CIFN were studied. STUDY APPRAISAL AND SYNTHESIS METHODS Studies were appraised based on methods of random sequence generation, allocation concealment, and blinding. The random effects model of DerSimonian and Laird was employed to run the meta-analysis. The end-point was sustained virological response (SVR). RESULTS Data of 10 RCTs including 1,600 subjects were extracted. High daily induction dose regimen of CIFN did not yield a higher rate of SVR than low daily induction dose treatment regimen, RR = 0.83 (95% CI 0.58-1.17). A dose of 9 μg thrice weekly (tiw) was associated with a significantly higher rate of SVR compared with 3 μg [RR = 3.14 (95% CI 1.68-5.58)][Symbol: see text]. Withdrawal rate was similar [RR = 1.28 (95% CI 0.65-2.50)] but dose modification was higher in 9 μg [RR = 3.22 (95% CI 1.08-9.60)]. A dose of 18/15 μg tiw was not more effective than 9 μg over a similar treatment duration [RR = 1.02 (95% CI 0. 87-1.19)]. LIMITATIONS Limitations include inadequate reporting of methodological information and side effects, lack of publication bias assessment due to the small number of studies in each analysis. CONCLUSIONS High dose daily induction therapy with CIFN is not superior to low dose therapy in terms of SVR. It seems that 9 μg tiw is the optimal treatment dose of CIFN for treatment of HCV infection. Optimal duration and safety profile of CIFN therapy have yet been elucidated.
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Martin CK, Hostetter JE, Hagan JJ. New opportunities for the management and therapy of hepatitis C in correctional settings. Am J Public Health 2010; 100:13-7. [PMID: 20007626 DOI: 10.2105/ajph.2008.147629] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatitis C in prison populations is now a major public health problem, and large numbers of correctional facilities have no comprehensive management program, often because of formidable projected costs and tightening budget constraints. The North Dakota Department of Corrections and Rehabilitation has operated a management and therapy program since 2002 using consensus interferon and ribavirin with 45% cost savings. The program has provided excellent sustained viral responses: 54.2% for genotype 1 hepatitis C, 75% for genotypes 2 and 3, and 63.6% overall.
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Affiliation(s)
- C Kent Martin
- Medcenter One Health Systems, 222 N 7th St, Bismark, ND 58501, USA.
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Du Y, Tian H, Gao XD, Yao WB. Pharmacokinetic properties of a 40 kDa branched polyethylene glycol-modified form of consensus interferon-α (PEG-CIFN) in rhesus monkeys. Biopharm Drug Dispos 2008; 29:481-4. [DOI: 10.1002/bdd.630] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Abstract
With more than 170 million individuals currently infected, HCV is a global pandemic, effecting approximately 3% of the entire world's population. HCV infection is a growing infectious disease pandemic with approximately 3-4 million new cases reported each year. Due to the persistent nature of the virus, 70-90% of infected individuals will develop chronic infection, which can lead to progressive liver disease including cirrhosis and hepatocellular carcinoma. Current standard treatment with a combination of IFN-alpha and ribavirin has improved the prognosis for many HCV sufferers; however, infection is very difficult to treat successfully and the protocol for treatment is neither simple, well tolerated nor economically favorable. Standard treatment can cost an average of US$22,000, and depending on genotype, as few as 42% of treated individuals will clear the infection. This collection of treatment issues combined with new concepts in immune therapy serve to underscore an urgent need for the development of improved immunotherapies, such as novel interferons, and support the possible development of therapeutic vaccines for the treatment of chronic HCV infection.
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Affiliation(s)
- Krystle Lang
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6100, USA.
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Abstract
BACKGROUND/AIMS In vitro studies in the subgenomic hepatitis C virus (HCV) replicon system have identified all-trans retinoic acid (ATRA) as a potential therapeutic against hepatitis C. Thus, the antiviral potential of this drug should be assessed in vivo. METHODS Twenty highly treatment experienced serotype 1 patients with non-response to conventional or pegylated interferon-alpha (Peg-/IFN-alpha) and ribavirin were randomly assigned to 12 weeks of monotherapy with ATRA (group A) or a combination of ATRA and PegIFN-alpha2a (group B). HCV RNA was assessed by bDNA assay and if negative by highly sensitive polymerase chain reaction. RESULTS During treatment, five of 10 patients in group A had a drop of viraemia >1log, while in group B after 8 weeks five of 10 dropped >2log, and three of 10 cleared HCV RNA from serum. Viraemia relapsed after treatment cessation. ATRA was rather well tolerated, with transient headache, dry skin and mucosa representing the most common side effects. CONCLUSIONS The viral load reduction under ATRA monotherapy, although limited and transient, supports the antiviral activity of ATRA. However, the rapid loss of HCV RNA in three of 10 previous non-responders under ATRA and PegIFN-alpha2a treatment demonstrates a strong additive or synergistic ATRA effect and calls for a controlled trial to assess the therapeutic potential of this drug.
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Affiliation(s)
- Wulf O Böcher
- I Department of Internal Medicine, Johannes Gutenberg University Hospital, Mainz, Germany.
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Gowen BB, Wong MH, Jung KH, Blatt LM, Sidwell RW. Prophylactic and therapeutic intervention of Punta Toro virus (Phlebovirus, Bunyaviridae) infection in hamsters with interferon alfacon-1. Antiviral Res 2008; 77:215-24. [PMID: 18222548 DOI: 10.1016/j.antiviral.2007.12.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2007] [Revised: 11/29/2007] [Accepted: 12/07/2007] [Indexed: 11/19/2022]
Abstract
Punta Toro virus (PTV) is a member of the Bunyaviridae family, genus Phlebovirus, related to the highly pathogenic Rift Valley fever virus (RVFV). It produces a disease in hamsters that models severe Rift Valley fever (RVF) in humans. The recent outbreak of RVF in Kenya stresses the need to identify prophylactic and therapeutic measures for preventing and treating severe forms of disease. To this end, interferon (IFN) alfacon-1 (consensus IFN-alpha) was evaluated in cell culture against RVFV and PTV, and in the hamster PTV infection model. Survival outcome following treatment initiated pre- and post-virus challenge and the suppression of viral burden and liver disease in infected hamsters was determined. Pre-treatment of cell cultures with IFN alfacon-1 induced marked antiviral activity against both viruses. Intraperitoneal treatment of hamsters initiated 4 h prior to infection with PTV was highly protective and greatly limited liver disease and systemic and liver viral burden. Complete protection from a highly lethal challenge dose was afforded by treatment initiated 36 h following viral inoculation. Although efficacy was much reduced, IFN alfacon-1 therapy was still beneficial when started as late as 3-5 days post-virus exposure. These studies suggest that IFN alfacon-1 may be an effective treatment for early intervention following infection with RVFV.
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Affiliation(s)
- Brian B Gowen
- Institute for Antiviral Research and Department of Animal, Dairy, and Veterinary Sciences, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA.
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Abstract
Patients with chronic hepatitis C virus (HCV) infection and disease-related complications - among them cirrhosis and liver failure - pose a particular management challenge. Some of these patients may fail to respond to current therapy (non-responders), and some are affected so severely that treatment puts them at an unacceptable risk for complications. Treatment with pegylated interferon (peg-IFN) plus ribavirin improves hepatic enzyme levels and eradicates the virus in approximately 50% of patients; however, a significant number of patients do not respond to therapy or relapse following treatment discontinuation. Several viral, hepatic and patient-related factors influence response to IFN therapy; many of these factors cannot be modified to improve long-term outcomes. Identifying risk factors and measuring viral load early in the treatment can help to predict response to IFN therapy and determine the need to modify or discontinue treatment. Retreatment options for patients who have failed therapy are limited. Retreatment with peg-IFN has been successful in some patients who exhibit an inadequate response to conventional IFN treatment, particularly those who have relapsed. Consensus IFN, another option in treatment-resistant patients, has demonstrated efficacy in the retreatment of non-responders and relapsers. Although the optimal duration of retreatment and the benefits and safety of maintenance therapy have not been determined, an extended duration is likely needed. This article reviews the risk factors for HCV treatment resistance and discusses the assessment and management of difficult-to-treat patients.
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Affiliation(s)
- Nyingi Kemmer
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0595, USA
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Sjogren MH, Sjogren R, Lyons MF, Ryan M, Santoro J, Smith C, Reddy KR, Bonkovsky H, Huntley B, Faris-Young S. Antiviral response of HCV genotype 1 to consensus interferon and ribavirin versus pegylated interferon and ribavirin. Dig Dis Sci 2007; 52:1540-7. [PMID: 17406822 DOI: 10.1007/s10620-007-9757-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2006] [Accepted: 01/01/2007] [Indexed: 12/09/2022]
Abstract
Achieving an antiviral response at a reasonable cost is a challenge in the treatment of patients with chronic hepatitis C. A previous study indicated that consensus interferon with ribavirin had promising activity against hepatitis C virus (HCV) genotype 1. The objective of this study was to determine the virologic response with consensus interferon or pegylated interferon alpha-2b plus weight-ribavirin in patients chronically infected with HCV genotype 1. Intention-to-treat analysis showed response in 37% and 41% of subjects treated with consensus interferon/ribavirin or pegylated interferon/ribavirin, respectively, with response rates of 42% and 44% observed in analysis of the per-protocol population, not a significant difference. Tolerability of the two treatment regimens was similar. In conclusion, both treatment regimens were safe and gave a similar antiviral response. It is possible that if consensus interferon is administered daily rather than three times weekly, eradication of HCV could be achieved in a larger proportion of patients infected with HCV genotype 1.
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Witthoeft T, Fuchs M, Ludwig D. Recent IV-drug users with chronic hepatitis C can be efficiently treated with daily high dose induction therapy using consensus interferon: An open-label pilot study. World J Gastroenterol 2007; 13:579-84. [PMID: 17278224 PMCID: PMC4065980 DOI: 10.3748/wjg.v13.i4.579] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the use of high dose consensus-interferon in combination with ribavirin in former iv drug users infected with hepatitis C.
METHODS: We started, before pegylated (PEG)-interferons were available, an open-label study to investigate the efficacy and tolerability of high dose induction therapy with consensus interferon (CIFN) and ribavirin in treatment of naiive patients with chronic hepatitis C. Fifty-eight patients who were former iv drug users, were enrolled receiving 18 μg of CIFN daily for 8 wk, followed by 9 μg daily for up to wk 24 or 48 and 800 mg of ribavirin daily. End point of the study was tolerability and eradication of the virus at wk 48 and sustained virological response at wk 72.
RESULTS: More than 62% of patients responded to the treatment with CIFN at wk 24 or 48, respectively, showing a negative qualitative PCR [genotype 1 fourteen patients (56%), genotype 2 five (50%), genotype 3 thirteen (87%), genotype 4 four (50%)]. Forty-eight percent of genotype 1 patients showed sustained virological response (SVR) six months after the treatment.
CONCLUSION: CIFN on a daily basis is well tolerated and side effects like leuko- and thrombocytopenia are moderate. End of therapy (EOT) rates are slightly lower than the newer standard therapy with pegylated interferons. CIFN on a daily basis might be a favourable therapy regimen for patients with GT1 and high viral load or for non-responders after failure of standard therapy.
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Affiliation(s)
- Th Witthoeft
- University Hospital Schleswig-Holstein Campus Luebeck, Department of Medicine I, Division of Gastroenterology, Luebeck 23538, Germany.
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Cornberg M, Deterding K, Manns MP. Present and future therapy for hepatitis C virus. Expert Rev Anti Infect Ther 2007; 4:781-93. [PMID: 17140355 DOI: 10.1586/14787210.4.5.781] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The treatment of hepatitis C virus (HCV) infection has developed enormously over recent years. Early treatment of acute HCV infection with interferon-alpha can prevent chronicity and a significant proportion of patients with chronic HCV can be cured with the current standard therapy consisting of pegylated interferon-alpha and ribavirin. However, the improvement of current treatment regimens and the development of new antiviral drugs will be essential within the next few years. This review focuses on the present and future concepts for treating HCV infection, including prevention of infection, antiviral therapy of acute and chronic HCV and the management of patients after liver transplantation.
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Affiliation(s)
- Markus Cornberg
- German Competence Network for Viral Hepatitis (Kompetenznetz Hepatitis), Medizinische Hochschule Hannover, Department of Gastroenterology, Hepatology, and Endocrinology, Carl-Neuberg Str. 1, D-30625 Hannover, Germany.
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Julander JG, Siddharthan V, Blatt LM, Schafer K, Sidwell RW, Morrey JD. Effect of exogenous interferon and an interferon inducer on western equine encephalitis virus disease in a hamster model. Virology 2006; 360:454-60. [PMID: 17118420 PMCID: PMC2040270 DOI: 10.1016/j.virol.2006.10.031] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2006] [Revised: 09/26/2006] [Accepted: 10/14/2006] [Indexed: 12/29/2022]
Abstract
Mice are used as models for western equine encephalitis virus (WEEV) infection, but high mortality is generally only seen with intracranial or intranasal challenge, while peripheral inoculation results in approximately 50% mortality and is not dose-dependent. Hamsters were therefore studied as a model for WEEV infection. Hamsters were highly sensitive to intraperitoneal (i.p.) infection with WEEV. Disease progression was rapid, and virus titers in serum, brain, liver, and kidney of infected hamsters peaked between 2 and 4 days post-virus inoculation (dpi). Foci of virus infection were detected in neurons of the cerebral cortex and midbrain. Pre-treatment i.p. with either interferon alfacon-1 (5 microg/kg/day) or with Ampligen (3.2 mg/kg/day) resulted in complete survival, reduced brain titers, and improved weight gain. This model of WEEV infection in hamsters appears to serve as a suitable model for the evaluation of potential therapeutic agents for the treatment of WEE disease.
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Affiliation(s)
- Justin G Julander
- Institute for Antiviral Research, Utah State University, Logan, UT 84322-5600, USA.
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23
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Alaimo G, Di Marco V, Ferraro D, Di Stefano R, Porrovecchio S, D'Angelo F, Calvaruso V, Craxì A, Almasio PL. Different doses of consensus interferon plus ribavirin in patients with hepatitis C virus genotype 1 relapsed after interferon monotherapy: A randomized controlled trial. World J Gastroenterol 2006; 12:6861-4. [PMID: 17106937 PMCID: PMC4087443 DOI: 10.3748/wjg.v12.i42.6861] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the efficacy of different schedules of consensus interferon (CIFN) plus ribavirin in retreating chronic hepatitis C patients who relapsed after recombinant interferon (rIFN) monotherapy.
METHODS: Forty-five patients (34 males and 11 females) with chronic hepatitis due to hepatitis C virus (HCV) genotype 1 who relapsed after a previous course of rIFN monotherapy were randomized to receive 9 μg CIFN three times per week for 52 wk (group A, n = 22) or 18 μg CIFN three times per week for 52 wk (group B, n = 23) in combination with ribavirin 800 to 1200 mg daily for 52 wk (according to body weight). Virological response was evaluated at week 24 (EVR), at the end of treatment (ETR) and at 76 wk (SVR).
RESULTS: By intention-to-treat analysis, subjects in group A had an EVR in 35% of cases, an ETR in 35% and a SVR in 27.3% of cases. Subjects in group B had an EVR in 32% of cases, an ETR in 35% and a SVR in 26.1% of cases. Treatment was stopped because of adverse effects (mostly intolerance) in 15 patients (6 in group A and 9 in group B). IFN dose reduction was needed in 2 patients (1 in group A and 1 in group B). Ribavirin dose was reduced in 2 patients in group A and 1 in group B respectively. Among the 15 subjects who received at least 80% of the intended schedule, the rate of SVR was 80% (6 in group A and 6 in group B).
CONCLUSION: CIFN in combination with ribavirin when given to HCV genotype 1 relapsers after rIFN monotherapy obtains an unsatisfactory rate of sustained viral clearance independently of dosage of the drug. This may be due to its scarce tolerability.
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Affiliation(s)
- Giuseppe Alaimo
- Cattedra di Gastroenterologia, University of Palermo, Piazza delle Cliniche 2, Palermo 90127, Italy
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Julander JG, Morrey JD, Blatt LM, Shafer K, Sidwell RW. Comparison of the inhibitory effects of interferon alfacon-1 and ribavirin on yellow fever virus infection in a hamster model. Antiviral Res 2006; 73:140-6. [PMID: 17049380 PMCID: PMC1828627 DOI: 10.1016/j.antiviral.2006.08.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2006] [Revised: 08/29/2006] [Accepted: 08/30/2006] [Indexed: 11/20/2022]
Abstract
Antiviral compounds were evaluated for efficacy against yellow fever virus (YFV) in a hamster model of YFV-induced liver disease. Challenge with a 10(2) 50% cell culture infectious doses of YFV resulted in a 50-80% mortality rate in female hamsters. Virus was detected by quantitative real-time RT-PCR (QRT-PCR) in liver, kidney, spleen and serum with peak titers on 4-6 days post-viral challenge (dpi). Serum levels of alkaline phosphatase, alanine aminotransferase (ALT), bilirubin, blood urea nitrogen, potassium and creatinine were significantly elevated, while serum levels of albumin, amylase, glucose, calcium, globulin, phosphorus, sodium and total protein were significantly reduced. Packed cell volume and white blood cell count were significantly elevated during the course of the infection. Intraperitoneal treatment of hamsters with 0.5-5 microg/kg/day interferon (IFN) alfacon-1, 100mg/kg/day viramidine or 50 mg/kg/day ribavirin, initiated 4h prior to YFV challenge, resulted in significant improvement in survival and serum ALT levels. Treatment with IFN alfacon-1 or ribavirin starting 2dpi, also significantly improved survival and serum ALT levels in hamsters challenged with YFV. Pre- and post-virus exposure treatment with IFN alfacon-1 was efficacious in improving disease in YFV-infected hamsters.
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Affiliation(s)
- Justin G Julander
- Institute for Antiviral Research, Utah State University, Logan, UT 84322-5600, United States.
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Krejsa C, Rogge M, Sadee W. Protein therapeutics: new applications for pharmacogenetics. Nat Rev Drug Discov 2006; 5:507-21. [PMID: 16763661 DOI: 10.1038/nrd2039] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Pharmacogenetic studies have traditionally focused on genes involved in processes that affect the pharmacokinetics of small-molecule drugs, such as drug metabolism. However, attention is shifting to the effects of genetic variations in drug targets and associated pathway components on drug responses. We describe how these variations are important for understanding differences in responses to the growing number of protein therapeutics that are entering clinical practice. Pharmacogenetic studies of these drugs are surveyed, and issues important to the success of such endeavours are discussed. As novel protein therapeutics are introduced, we anticipate that the use of pharmacogenetics will assume a key role in their development and clinical application.
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Affiliation(s)
- Cecile Krejsa
- ZymoGenetics, Inc., 1201 Eastlake Avenue East, Seattle, Washington 98102-3702, USA.
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Sjogren MH. Management of hepatitis C. Gastroenterology 2006; 131:332; author reply 332-3. [PMID: 16831622 DOI: 10.1053/j.gastro.2006.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Cornberg M, Hadem J, Herrmann E, Schuppert F, Schmidt HHJ, Reiser M, Marschal O, Steffen M, Manns MP, Wedemeyer H. Treatment with daily consensus interferon (CIFN) plus ribavirin in non-responder patients with chronic hepatitis C: a randomized open-label pilot study. J Hepatol 2006; 44:291-301. [PMID: 16360972 DOI: 10.1016/j.jhep.2005.10.021] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2005] [Revised: 10/06/2005] [Accepted: 10/24/2005] [Indexed: 12/26/2022]
Abstract
BACKGROUND/AIMS Therapeutic options for hepatitis C non-responder patients are limited. METHODS We initiated an open-label pilot study to investigate the efficacy of CIFN plus ribavirin on viral kinetics, sustained virological response (SVR), and histological response in hepatitis C non-responder patients. Seventy-seven patients were enrolled to receive CIFN given daily in combination with 1000/1200 mg ribavirin. An 8-week induction-dosing regimen of 18 microg CIFN, followed by 9 microg for 40 weeks was compared to 9 microg CIFN for 48 weeks. 90% of patients were infected with HCV-genotype 1. RESULTS Overall, 82% of the patients demonstrated an early virological response, 65% had an end-of-treatment response, and the SVR was 30%. Interferon/ribavirin non-responders demonstrated a SVR of 22%. Induction-dosing resulted in a greater first-phase HCV-RNA decay that, however, did not translate to better SVRs, presumably due to more dose modifications. High ALT, younger age, and second-phase viral kinetics were associated with SVR. Only sustained responders and relapse patients showed an improved liver histology. CONCLUSIONS Daily dosing of CIFN plus ribavirin may be a promising concept for selected non-responder patients before considering therapies which are anti-viral but not curative. However, motivation and compliance are requisites and a CIFN induction is not required.
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Affiliation(s)
- Markus Cornberg
- Abt. Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
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Saito H, Tada S, Ebinuma H, Ishii H, Kashiwazaki K, Nishida J, Yoshida T, Zeki S, Yoshida H, Yoshioka M, Inagaki Y, Kumagai N, Hibi T. Induction therapy with twice-daily interferon-beta does not improve the therapeutic efficacy of consensus interferon monotherapy for chronic hepatitis C. Keio J Med 2006; 55:111-7. [PMID: 17008803 DOI: 10.2302/kjm.55.111] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We examined therapeutic superiority of induction therapy with twice-daily IFN-beta (3X2=6 million units/day) onto 6-months consensus interferon monotherapy for chronic hepatitis C. Patients were randomly assigned to monotherapy without (group I, n=16) and with induction therapy (group II, n=12). The mean age of group II was older than that of group I, and other baseline condition was not statistically significant. Sustained virological response (SVR) rates of group I and II were 81.3% (13/16) and 58.3% (7/12), respectively (p=0.365). SVR rates in patients with genotype 1b were 66.7% (4/6) and 0% (0/2, because of drop-out), and those with high viral load were 70% (7/10) and 75% (6/8) in group I and II, respectively (p=1.000). Drop-out rates during therapy were 6.3% (1/16) and 33.3% (4/12) in group I and II, respectively (p=0.176). Age less than 50 years was the only independent factor that was shown by multivariate logistic model analysis to be associated with a sustained virological response. Although randomization failed to produce and equal age distribution in the two groups in this study, our results suggest that induction therapy with twice-daily IFN-beta has no beneficial effect on the efficacy of monotherapy with consensus interferon, probably because of the higher drop-out rates and incidence of adverse reactions with induction therapy.
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Affiliation(s)
- Hidetsugu Saito
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
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Abstract
The development of new treatment strategies for the therapy of hepatitis C is an unmet need. There has already been an enormous improvement in the therapy of chronic hepatitis C since the early 1990s, but the sustained virologic response rates are still unsatisfactory for certain patient groups. Novel therapeutic strategies, especially for the difficult-to-treat patients, are currently being tested. This review discusses the latest achievements in the treatment of chronic heptatis C.
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Affiliation(s)
- Markus Cornberg
- Kompentenznetz Hepatitis, Medizinische Hochschule Hannover, Departments of Gastroenterology, Hepatology and Endocrinology, Carl-Neuberg Str. 1, D-30625 Hannover, Germany
| | - Michael P Manns
- Kompentenznetz Hepatitis, Medizinische Hochschule Hannover, Departments of Gastroenterology, Hepatology and Endocrinology, Carl-Neuberg Str. 1, D-30625 Hannover, Germany
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