Amide-to-ester Substitution As a Stable Alternative to N-methylation for Increasing Membrane Permeability in Cyclic Peptides

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Mar 18

PMID 36932083

Authors

Yuki Hosono

Satoshi 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

Affiliations

Soon will be listed here.

Abstract

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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