膜
酰胺
化学
环肽
渗透
膜透性
分子动力学
肽键
磁导率
生物物理学
肽
立体化学
组合化学
有机化学
生物化学
计算化学
生物
作者
Yuki Hosono,S. Uchida,Moe Shinkai,Chad E. Townsend,Colin N. Kelly,Matthew R. Naylor,Hsiau‐Wei Lee,Kayoko Kanamitsu,Mayumi Ishii,Ryosuke Ueki,Takumi Ueda,Koh Takeuchi,Masatake Sugita,Yutaka Akiyama,Scott R. Lokey,Jumpei Morimoto,Shinsuke Sando
标识
DOI:10.1038/s41467-023-36978-z
摘要
Naturally occurring peptides with high membrane permeability often have ester bonds on their backbones. However, the impact of amide-to-ester substitutions on the membrane permeability of peptides has not been directly evaluated. Here we report the effect of amide-to-ester substitutions on the membrane permeability and conformational ensemble of cyclic peptides related to membrane permeation. Amide-to-ester substitutions are shown to improve the membrane permeability of dipeptides and a model cyclic hexapeptide. NMR-based conformational analysis and enhanced sampling molecular dynamics simulations suggest that the conformational transition of the cyclic hexapeptide upon membrane permeation is differently influenced by an amide-to-ester substitution and an amide N-methylation. The effect of amide-to-ester substitution on membrane permeability of other cyclic hexapeptides, cyclic octapeptides, and a cyclic nonapeptide is also investigated to examine the scope of the substitution. Appropriate utilization of amide-to-ester substitution based on our results will facilitate the development of membrane-permeable peptides.
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