Copyright
©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. Nov 6, 2015; 6(4): 213-222
Published online Nov 6, 2015. doi: 10.4292/wjgpt.v6.i4.213
Published online Nov 6, 2015. doi: 10.4292/wjgpt.v6.i4.213
Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis
Kunwar Shailubhai, Vaseem Palejwala, John A Foss, Stephen Comiskey, R and D Center, Synergy Pharmaceuticals Inc., Doylestown, PA 18902, United States
Krishna Priya Arjunan, Sayali Saykhedkar, Bradley Nefsky, Baruch Blumberg Institute, PA Biotechnology Center, Doylestown, PA 18902, United States
Gary S Jacob, Synergy Pharmaceuticals Inc., New York, NY 10170, United States
Scott E Plevy, Departments of Medicine, Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States
Author contributions: Shailubhai K, Arjunan KP, Saykhedkar S, Nefsky B, Foss JA and Comiskey S contributed to study concept, design, data acquisition, analysis and interpretation; Shailubhai K, Palejwala V, Jacob GS and Plevy SE contributed to manuscript preparation, critical revision and provided important intellectual content.
Institutional review board statement: Experiments reported in this manuscript did not involve human samples and hence institutional review is not applicable.
Institutional animal care and use committee statement: Studies employing BALB/c and TCRα-/- mice were performed under the direct supervision of Doctor Scott Plevy at the University of Pittsburgh School of Medicine (Pittsburg, PA). Animals obtained from Jackson Laboratories (Bar Harbor, ME) were housed in accordance with guidelines from the American Association for Laboratory Animal Care and Research. Institutional Animal Care and Use Committee of the University of Pittsburgh approved all protocols. Epistem Ltd (Manchester, United Kingdom) conducted DSS and TNBS-induced colitis studies employing BDF1 mice. Animals obtained from Harlan Laboratories, United Kingdom, were housed individually in ventilated cages in a specific pathogen-free barrier unit in compliance with animal welfare regulations. All procedures were certified according to the United Kingdom Home Office (Animal Procedures) Act 1986.
Conflict-of-interest statement: Shailubhai K, Foss JA, Comiskey S, Palejwala V and Jacob GS are employees of Synergy Pharmaceuticals. Nefsky B, Arjunan KP, Saykhedkar S have no conflict of interest. Plevy SE received compensation as a consultant from Synergy Pharmaceuticals Inc.
Data sharing statement: Authors agree to share the raw data included in the manuscript with other researchers.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Kunwar Shailubhai, Doctor of Philosophy, Chief Scientific Officer, R and D Center, Synergy Pharmaceuticals Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States. shailu@synergypharma.com
Telephone: +1-215-5896308 Fax: +1-215-5896309
Received: April 21, 2015
Peer-review started: April 21, 2015
First decision: July 1, 2015
Revised: July 16, 2015
Accepted: August 13, 2015
Article in press: August 14, 2015
Published online: November 6, 2015
Peer-review started: April 21, 2015
First decision: July 1, 2015
Revised: July 16, 2015
Accepted: August 13, 2015
Article in press: August 14, 2015
Published online: November 6, 2015
Core Tip
Core tip: Plecanatide (SP-304) and dolcanatide (SP-333) are structurally close analogs of the human endogenous natriuretic peptide uroguanylin, a ligand of guanylate cyclase-C (GC-C). Here we report that oral treatment with plecanatide or dolcanatide effectively ameliorates colitis in acute and chronic models of murine experimental colitis. The anti-inflammatory activity of plecanatide and dolcanatide was comparable to that achieved after treatment with sulfasalazine or 5-amino salicylic acid. This is the first-ever study reporting the therapeutic utility of GC-C agonists as a new class of orally delivered and mucosally active drug candidates for the treatment and management of inflammatory bowel diseases in humans.