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

Autor: Hosono, Yuki, Uchida, Satoshi, Shinkai, Moe, Townsend, Chad E., Kelly, Colin N., Naylor, Matthew R., Lee, Hsiau-Wei, Kanamitsu, Kayoko, Ishii, Mayumi, Ueki, Ryosuke, Ueda, Takumi, Takeuchi, Koh, Sugita, Masatake, Akiyama, Yutaka, Lokey, Scott R., Morimoto, Jumpei, Sando, Shinsuke
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Zdroj: Nature Communications; 3/17/2023, Vol. 14, p1-14, 14p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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