Targeted protein degradation as a novel therapeutic strategy against infectious diseases

Abstract

Targeted protein degradation (TPD) represents an emerging antimicrobial strategy that is predominantly still in preclinical development stages. Chimeric molecules (i.e., PROteolysis-TArgeting Chimera [PROTACs]) that can direct molecular targets for degradation by hijacking a cell's proteolytic machinery offer significant advantages over traditional small-molecule therapeutics. These include diversifying the druggable proteome by targeting previously 'undruggable' non-enzymatic and structural proteins, lowering the effective therapeutic concentration, enabling lower drug concentrations, and delaying resistance development. Recent reports of BacPROTACs that are active against Mycobacterium tuberculosis have set the stage to exploit TPD for antimicrobial drug development, yet despite its clear relevance to African-endemic diseases challenged by multidrug resistance-notably HIV, tuberculosis, and malaria-TPD-based infectious disease therapeutic development remains in its early stages. This review highlights the recent advances in the development and application of PROTACs as antimicrobials and provides an outlook for TPD's strategic value in addressing the growing threat posed by drug-resistant pathogens.