Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides

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. Naturally occurring peptides with high membrane permeability often have backbone ester bonds. Here, the authors investigated the effect of an amide-to-ester substitution on membrane permeability of peptides and found the substitution is useful for improving membrane permeability of cyclic peptides.

• Publication year

  2023

• Venue

  Nature Communications

• Publication date

  2023-03-17

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1038/s41467-023-36978-zPMID 36932083PMCID 10023679
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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