Bifunctional modalities for repurposing protein function

Abstract

Nature takes advantage of induced proximity to perform various functions. Taking inspiration from nature, we can also trigger desired biological processes using bifunctional small molecules that artificially induce proximity. For example, bifunctional small molecules have been designed to trigger the ubiquitin-dependent proteasomal degradation of intracellular proteins. Now, recent classes of bifunctional compounds have been developed to degrade extracellular targets, membrane proteins, damaged organelles, and RNA by recruiting alternative degradation pathways. In addition to inducing degradation, bifunctional modalities can change phosphorylation and glycosylation states to evoke a biological response. In this review, we highlight recent advances in these innovative classes of compounds that build on a rich history of chemical inducers of dimerization. We anticipate that more bifunctional molecules, which induce or remove posttranslational modifications, to endow neo-functionalities will emerge.

Keywords: PROTACs; bifunctional molecules; molecular glues; posttranslational modifications; protein degradation; proximity induction.