Enhanced Permeability and Binding Activity of Isobutylene-Grafted Peptides

Chembiochem : a European Journal of Chemical Biology
Shuang SunGonçalo J L Bernardes

Abstract

We present a new peptide-macrocyclization strategy with an isobutylene graft. The reaction is mild and proceeds rapidly and efficiently both for linear and cyclic peptides. The resulting isobutylene-grafted peptides possess improved passive membrane permeability due to the shielding of the polar backbone of the amides, as demonstrated by NMR spectroscopy and molecular dynamics simulations. The isobutylene-stapled structures are fully stable in human plasma and in the presence of glutathione. This strategy can be applied to bioactive cyclic peptides such as somatostatin. Importantly, we found that structural preorganization forced by the isobutylene graft leads to a significant improvement in binding. The combined advantages of directness, selectivity, and smallness could allow application to peptide macrocyclization based on this attachment of the isobutylene graft.

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Citations

Oct 10, 2018·Angewandte Chemie·Shuang SunGonçalo J L Bernardes
Dec 13, 2018·Organic & Biomolecular Chemistry·Shuang SunGonçalo J L Bernardes
Jul 31, 2019·Journal of the American Chemical Society·Alec H ChristianF Dean Toste
Aug 28, 2021·RSC Medicinal Chemistry·Clément Bechtler, Christina Lamers

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Methods Mentioned

BETA
CLIPS
NMR
circular dichroism

Software Mentioned

AMBER
MD

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