期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 23, 期 27, 页码 6483-6489出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201700745
关键词
antibodies; oxetanes; protein modifications; small oxygen heterocycles; sulfur
资金
- European Commission
- MINECO Spain
- FCT Portugal
- EPSRC
- ERC
- EPSRC [EP/M003647/1] Funding Source: UKRI
- Cancer Research UK [17242] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/M003647/1] Funding Source: researchfish
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.
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