On the Utility of Chemical Strategies to Improve Peptide Gut Stability
Abstract
Inherent susceptibility of peptides to enzymatic degradation in the gastrointestinal tract is a key bottleneck in oral peptide drug development. Here, we present a systematic analysis of (i) the gut stability of disulfide-rich peptide scaffolds, orally administered peptide therapeutics, and well-known neuropeptides and (ii) medicinal chemistry strategies to improve peptide gut stability. Among a broad range of studied peptides, cyclotides were the only scaffold class to resist gastrointestinal degradation, even when grafted with non-native sequences. Backbone cyclization, a frequently applied strategy, failed to improve stability in intestinal fluid, but several site-specific alterations proved efficient. This work furthermore highlights the importance of standardized gut stability test conditions and suggests defined protocols to facilitate cross-study comparison. Together, our results provide a comparative overview and framework for the chemical engineering of gut-stable peptides, which should be valuable for the development of orally administered peptide therapeutics and molecular probes targeting receptors within the gastrointestinal tract.
Introduction
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Thomas Kremsmayr, Aws Aljnabi, Juan B. Blanco-Canosa, Hue N. T. Tran, Nayara Braga Emidio, and Markus Muttenthaler, Journal of Medicinal Chemistry 2022 65 (8), 6191-6206
DOI: 10.1021/acs.jmedchem.2c00094
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