Titel
Improving the Gastrointestinal Stability of Linaclotide
Autor*in
Asa Andersson
Institute for Molecular Bioscience, The University of Queensland
... show all
Abstract
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.
Stichwort
DisulfidesOrganic polymersPeptides and proteinsStabilityTherapeutics
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
phaidra.univie.ac.at/o:1536472
Erschienen in
Titel
Journal of Medicinal Chemistry
Band
64
Ausgabe
12
ISSN
0022-2623
Erscheinungsdatum
2021
Seitenanfang
8384
Seitenende
8390
Publication
American Chemical Society (ACS)
Fördergeber
European Union (all programmes) — 714366
Vienna Science and Technology Fund (WWTF) — LS18-053
Erscheinungsdatum
2021
Zugänglichkeit
Rechte
Rechteangabe
© 2021 The Authors
Universität Wien | Universitätsring 1 | 1010 Wien | T
+43-1-4277-0