Synthetic modification of protein surfaces to mediate induced-proximity pharmacology

Molecular glues and bifunctional small molecules, such as targeted protein degraders, induce protein proximity to mediate gain-of-function pharmacology. Emerging technologies that synthetically manipulate protein surfaces to create neoproteins, and the development of covalent chemical probes for intra- and inter-protein surface labeling are described. Ligand-directed protein surface modification strategies have the potential to enhance the induced-proximity pharmacology toolkit and expand the druggable proteome, and this Opinion considers the opportunities and challenges that lie ahead.