General dual functionalisation of biomacromolecules a cysteine bridging strategy

• Published in: Organic & biomolecular chemistry 2020-06, Vol.18 (22), p.4224-423
• Main Authors: Walsh, Stephen J, Iegre, Jessica, Seki, Hikaru, Bargh, Jonathan D, Sore, Hannah F, Parker, Jeremy S, Carroll, Jason S, Spring, David R
• Format: Article
• Language: English
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d0ob00907e

Site-selective modification of peptides and proteins has resulted in the development of a host of novel tools for the study of cellular systems or the synthesis of enhanced biotherapeutics. There is a need for useful methodologies that enable site-selective modification of native peptides or proteins, which is even more prevalent when modification of the biomolecule with multiple payloads is desired. Herein, we report the development of a novel dual functional divinylpyrimidine (dfDVP) platform that enables robust and modular modification of peptides, antibody fragments and antibodies. These biomacromolecules could be easily functionalised with a range of functional payloads ( e.g. fluorescent dyes, cytotoxic warheads or cell-penetrating tags). Importantly, the dual functionalised peptides and antibodies demonstrated exquisite bioactivity in a range of in vitro cellular assays, showcasing the enhanced utility of these bioactive conjugates. A general method that facilitates the modular dual functionalisation of a range of peptides and proteins is reported.