title: 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.|Current address: Departament de Química Analítica i Química Orgànica, Facultat de Química, Universitat Rovira i Virgili, C/ Marcel⋅lí Domingo 1, 43007, Tarragona, Spain.
authors.forename: Omar
authors.identifier: http://orcid.org/0000-0002-0768-8309
authors.initials: O
authors.lastname: Boutureira
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
authors.forename: Nuria
authors.initials: N
authors.lastname: Martínez-Sáez
authors.affiliation: Li Ka Shing Centre, Cancer Research (UK) Cambridge Institute, Robinson Way, CB2 0RE, Cambridge, UK.|Department of Biochemistry, University of Cambridge, Tennis Court Road, CB2 1GA, Cambridge, UK.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brindle
authors.affiliation: Li Ka Shing Centre, Cancer Research (UK) Cambridge Institute, Robinson Way, CB2 0RE, Cambridge, UK.
authors.forename: André A
authors.initials: AA
authors.lastname: Neves
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.|Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006, Logroño, Spain.
authors.forename: Francisco
authors.identifier: http://orcid.org/0000-0001-5597-8127
authors.initials: F
authors.lastname: Corzana
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal.
authors.forename: Gonçalo J L
authors.identifier: http://orcid.org/0000-0001-6594-8917
authors.initials: GJL
authors.lastname: Bernardes
mesh_terms: D000478:Alkylation; D000906:Antibodies / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003545:Cysteine / Q000737:chemistry; D004988:Ethers, Cyclic / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D020349:Surface Plasmon Resonance
chemical_list: D000906:Antibodies; D004988:Ethers, Cyclic; D011506:Proteins; C005287:oxetane; D003545:Cysteine
keywords: antibodies; oxetanes; protein modifications; small oxygen heterocycles; sulfur