Targeted Protein Degradation: The New Frontier of Antimicrobial Discovery?

Abstract

Targeted protein degradation aims to hijack endogenous protein quality control systems to achieve direct knockdown of protein targets. This exciting technology utilizes event-based pharmacology to produce therapeutic outcomes, a feature that distinguishes it from classical occupancy-based inhibitor agents. Early degrader candidates display resilience to mutations while possessing potent nanomolar activity and high target specificity. Paired with the rapid advancement of our knowledge in the factors driving targeted degradation, the expansion of this style of therapeutic agent to a range of disease indications is eagerly awaited. In particular, the area of antibiotic discovery is sorely lacking in novel approaches, with the Antimicrobial Resistance (AMR) crisis looming as the next potential global health calamity. Here, the current advances in targeted protein degradation are highlighted, and potential approaches for designing novel antimicrobial protein degraders are proposed, ranging from adaptations of current strategies to completely novel approaches to targeted protein degradation.