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Site-Selective Modification of Proteins with Oxetanes.

ABSTRACT: Oxetanes are four-membered ring oxygen heterocycles that are advantageously used in medicinal chemistry as modulators of physicochemical properties of small molecules. Herein, we present a simple method for the incorporation of oxetanes into proteins through chemoselective alkylation of cysteine. We demonstrate a broad substrate scope by reacting proteins used as apoptotic markers and in drug formulation, and a therapeutic antibody with a series of 3-oxetane bromides, enabling the identification of novel handles (S-to-S/N rigid, non-aromatic, and soluble linker) and reactivity modes (temporary cysteine protecting group), while maintaining their intrinsic activity. The possibility to conjugate oxetane motifs into full-length proteins has potential to identify novel drug candidates as the next-generation of peptide/protein therapeutics with improved physicochemical and biological properties.

SUBMITTER: Boutureira O

PROVIDER: S-EPMC5434895 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Site-Selective Modification of Proteins with Oxetanes.

Boutureira Omar O Martínez-Sáez Nuria N Brindle Kevin M KM Neves André A AA Corzana Francisco F Bernardes Gonçalo J L GJL

Chemistry (Weinheim an der Bergstrasse, Germany) 20170329 27

Oxetanes are four-membered ring oxygen heterocycles that are advantageously used in medicinal chemistry as modulators of physicochemical properties of small molecules. Herein, we present a simple method for the incorporation of oxetanes into proteins through chemoselective alkylation of cysteine. We demonstrate a broad substrate scope by reacting proteins used as apoptotic markers and in drug formulation, and a therapeutic antibody with a series of 3-oxetane bromides, enabling the identification ...[more]

PMID: 28261889

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