Site-Selective Modification of Proteins with Oxetanes
Chemistry - A European Journal
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Boutureira, O., Martínez-Sáez, N., Brindle, K., Neves, A., Corzana, F., & Lopes Bernardes, G. (2017). Site-Selective Modification of Proteins with Oxetanes. Chemistry - A European Journal https://doi.org/10.1002/chem.201700745
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.
antibodies, oxetanes, protein modifications, small oxygen heterocycles, sulfur
We thank the European Commission (Marie Skłodowska-Curie ITN ProteinConjugates; Marie Curie IEF to O.B.), MINECO Spain (Salvador de Madariaga mobility grant to F. C.), FCT Portugal (FCT Investigator to G.J.L.B.), and the EPSRC for financial support. We thank Albumedix, Ltd. for providing Recombumin and Genentech, Inc. for providing 4D5 LC-V205C Thiomab. We also thank Dr. Mike Deery and Ms. Julie Howard for help with mass spectrometry analysis. G.J.L.B. is a Royal Society URF and the recipient of an ERC Starting Grant (TagIt).
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675007)
European Commission Horizon 2020 (H2020) ERC (676832)
External DOI: https://doi.org/10.1002/chem.201700745
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264048
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International