Site-Selective Modification of Proteins with Oxetanes

Identifier:  imarina:2840288

Handle: https://hdl.handle.net/20.500.11797/imarina2840288

Authors:  Boutureira, Omar; Martinez-Saez, Nuria; Brindle, Kevin M; Neves, Andre A; Corzana, Francisco; Bernardes, Goncalo J L

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.