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

Yuki HosonoSatoshi UchidaMoe ShinkaiChad E TownsendColin N KellyMatthew R NaylorHsiau-Wei LeeKayoko KanamitsuMayumi IshiiRyosuke UekiTakumi UedaKoh TakeuchiMasatake SugitaYutaka AkiyamaScott R LokeyJumpei MorimotoShinsuke Sando
Published in: Nature communications (2023)
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.
Keyphrases
  • molecular dynamics simulations
  • molecular dynamics
  • magnetic resonance
  • dna methylation
  • high resolution
  • gene expression
  • amino acid
  • solid state
  • transition metal