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Enhanced Permeability and Binding Activity of Isobutylene-Grafted Peptides.

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.

SUBMITTER: Sun S

PROVIDER: S-EPMC5813187 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Enhanced Permeability and Binding Activity of Isobutylene-Grafted Peptides.

Sun Shuang S Compañón Ismael I Martínez-Sáez Nuria N Seixas João D JD Boutureira Omar O Corzana Francisco F Bernardes Gonçalo J L GJL

Chembiochem : a European journal of chemical biology 20171122 1

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. Thi ...[more]

PMID: 29105291

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