肽
化学
胃肠道
计算生物学
G蛋白偶联受体
受体
生物化学
代谢稳定性
组合化学
药理学
体外
生物
作者
Thomas Kremsmayr,Aws Aljnabi,Juan B. Blanco‐Canosa,Hue N. T. Tran,Nayara Braga Emídio,Markus Muttenthaler
标识
DOI:10.1021/acs.jmedchem.2c00094
摘要
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.
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