On the Utility of Chemical Strategies to Improve Peptide Gut Stability

Inherent susceptibility of peptides to enzymaticdegradation in the gastrointestinal tract is a key bottleneck in oralpeptide drug development. Here, we present a systematic analysis of (i)the gut stability of disulfide-rich peptide scaffolds, orally administeredpeptide therapeutics, and well-known neuropeptides and (ii) medicinalchemistry strategies to improve peptide gut stability. Among a broadrange of studied peptides, cyclotides were the only scaffold class toresist gastrointestinal degradation, even when grafted with non-nativesequences. Backbone cyclization, a frequently applied strategy, failed toimprove stability in intestinalfluid, but several site-specific alterationsproved efficient. This work furthermore highlights the importance ofstandardized gut stability test conditions and suggests definedprotocols to facilitate cross-study comparison. Together, our results provide a comparative overview and framework for thechemical engineering of gut-stable peptides, which should be valuable for the development of orally administered peptidetherapeutics and molecular probes targeting receptors within the gastrointestinal tract.