1. Rapid and robust cysteine bioconjugation with vinylheteroarenes
- Author
-
Seki, Hikaru, Walsh, Stephen J, Bargh, Jonathan D, Parker, Jeremy S, Carroll, Jason, Spring, David R, Seki, Hikaru [0000-0001-9663-7791], Walsh, Stephen J [0000-0002-3164-1519], Bargh, Jonathan D [0000-0003-3023-2569], Parker, Jeremy S [0000-0002-4758-3181], Carroll, Jason [0000-0003-3643-0080], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository
- Subjects
chemistry.chemical_classification ,Bioconjugation ,34 Chemical Sciences ,Chemical biology ,3405 Organic Chemistry ,General Chemistry ,Combinatorial chemistry ,Small molecule ,Amino acid ,Chemistry ,chemistry ,Reagent ,Generic health relevance ,3404 Medicinal and Biomolecular Chemistry ,Linker ,Conjugate ,Cysteine ,Biotechnology - Abstract
Methods for residue-selective and stable modification of canonical amino acids enable the installation of distinct functionality which can aid in the interrogation of biological processes or the generation of new therapeutic modalities. Herein, we report an extensive investigation of reactivity and stability profiles for a series of vinylheteroarene motifs. Studies on small molecule and protein substrates identified an optimum vinylheteroarene scaffold for selective cysteine modification. Utilisation of this lead linker to modify a number of protein substrates with various functionalities, including the synthesis of a homogeneous, stable and biologically active antibody–drug conjugate (ADC) was then achieved. The reagent was also efficient in labelling proteome-wide cysteines in cell lysates. The efficiency and selectivity of these reagents as well as the stability of the products makes them suitable for the generation of biotherapeutics or studies in chemical biology., Vinylheteroarene linkers can chemoselectively modify cysteine residues in proteins and antibodies. These linkers give stable bioconjugates, and were used to synthesise efficacious antibody-drug conjugates.
- Published
- 2021
- Full Text
- View/download PDF