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

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 () and Shinsuke Sando ()
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Yuki Hosono: The University of Tokyo
Satoshi Uchida: The University of Tokyo
Moe Shinkai: The University of Tokyo
Chad E. Townsend: University of California
Colin N. Kelly: University of California
Matthew R. Naylor: University of California
Hsiau-Wei Lee: University of California
Kayoko Kanamitsu: The University of Tokyo
Mayumi Ishii: The University of Tokyo
Ryosuke Ueki: The University of Tokyo
Takumi Ueda: The University of Tokyo
Koh Takeuchi: The University of Tokyo
Masatake Sugita: Tokyo Institute of Technology
Yutaka Akiyama: Tokyo Institute of Technology
Scott R. Lokey: University of California
Jumpei Morimoto: The University of Tokyo
Shinsuke Sando: The University of Tokyo

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36978-z

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