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Improving the Gastrointestinal Stability of Linaclotide

[Image: see text] High susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs in gastrointestinal disorders. Linaclotide is an orally administered peptide drug for the treatment of irritable bowel syndrome with constipation (IBS-C)...

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Autores principales: Braga Emidio, Nayara, Tran, Hue N. T., Andersson, Asa, Dawson, Philip E., Albericio, Fernando, Vetter, Irina, Muttenthaler, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237258/
https://www.ncbi.nlm.nih.gov/pubmed/33979161
http://dx.doi.org/10.1021/acs.jmedchem.1c00380
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author Braga Emidio, Nayara
Tran, Hue N. T.
Andersson, Asa
Dawson, Philip E.
Albericio, Fernando
Vetter, Irina
Muttenthaler, Markus
author_facet Braga Emidio, Nayara
Tran, Hue N. T.
Andersson, Asa
Dawson, Philip E.
Albericio, Fernando
Vetter, Irina
Muttenthaler, Markus
author_sort Braga Emidio, Nayara
collection PubMed
description [Image: see text] High susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs in gastrointestinal disorders. Linaclotide is an orally administered peptide drug for the treatment of irritable bowel syndrome with constipation (IBS-C) and abdominal pain. Linaclotide is however degraded in the intestinal environment within 1 h, and improvements in gastrointestinal stability might enhance its therapeutic application. We therefore designed and synthesized a series of linaclotide analogues employing a variety of strategic modifications and evaluated their gastrointestinal stability and pharmacological activity at its target receptor guanylate cyclase-C. All analogues had substantial improvements in gastrointestinal half-lives (>8 h vs linaclotide 48 min), and most remained active at low nanomolar concentrations. This work highlights strategic approaches for the development of gut-stable peptides toward the next generation of orally administered peptide drugs for the treatment of gastrointestinal disorders.
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spelling pubmed-82372582021-07-06 Improving the Gastrointestinal Stability of Linaclotide Braga Emidio, Nayara Tran, Hue N. T. Andersson, Asa Dawson, Philip E. Albericio, Fernando Vetter, Irina Muttenthaler, Markus J Med Chem [Image: see text] High susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs in gastrointestinal disorders. Linaclotide is an orally administered peptide drug for the treatment of irritable bowel syndrome with constipation (IBS-C) and abdominal pain. Linaclotide is however degraded in the intestinal environment within 1 h, and improvements in gastrointestinal stability might enhance its therapeutic application. We therefore designed and synthesized a series of linaclotide analogues employing a variety of strategic modifications and evaluated their gastrointestinal stability and pharmacological activity at its target receptor guanylate cyclase-C. All analogues had substantial improvements in gastrointestinal half-lives (>8 h vs linaclotide 48 min), and most remained active at low nanomolar concentrations. This work highlights strategic approaches for the development of gut-stable peptides toward the next generation of orally administered peptide drugs for the treatment of gastrointestinal disorders. American Chemical Society 2021-05-12 2021-06-24 /pmc/articles/PMC8237258/ /pubmed/33979161 http://dx.doi.org/10.1021/acs.jmedchem.1c00380 Text en © 2021 The Authors. Published by American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Braga Emidio, Nayara
Tran, Hue N. T.
Andersson, Asa
Dawson, Philip E.
Albericio, Fernando
Vetter, Irina
Muttenthaler, Markus
Improving the Gastrointestinal Stability of Linaclotide
title Improving the Gastrointestinal Stability of Linaclotide
title_full Improving the Gastrointestinal Stability of Linaclotide
title_fullStr Improving the Gastrointestinal Stability of Linaclotide
title_full_unstemmed Improving the Gastrointestinal Stability of Linaclotide
title_short Improving the Gastrointestinal Stability of Linaclotide
title_sort improving the gastrointestinal stability of linaclotide
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237258/
https://www.ncbi.nlm.nih.gov/pubmed/33979161
http://dx.doi.org/10.1021/acs.jmedchem.1c00380
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