LAUSR

Infectious diseases remain a major burden to global health. Despite implementation of successful vaccination campaigns and efficient drugs, the increasing emergence of pathogenic vaccine or treatment resistance demands novel therapeutic strategies. The development of traditional therapies using small molecule drugs is based on modulating protein function and activity through occupation of active sites, such as enzyme inhibition or ligand-receptor binding. These pre-requisites result in the majority of host and pathogenic disease-relevant, non-enzymatic and structural proteins being labelled 'undruggable'. Targeted protein degradation (TPD) emerged as a powerful strategy to eliminate proteins of interest, including those of the 'undruggable' variety. Proteolysis-targeting chimeras (PROTACs) are rationally designed hetero-bifunctional small molecules that exploit the cellular ubiquitin-proteasome system to specifically mediate the highly selective and effective degradation of target proteins. PROTACs have shown remarkable results in the degradation of various cancer-associated proteins and several candidates are already in clinical development. Significantly, PROTAC mediated TPD holds great potential for targeting and modulating pathogenic proteins, especially in the face of increasing drug-resistance to the best-in-class treatments. In this review, we discuss advances in development of TPD in the context of targeting the host-pathogen interface and speculate on their potential use to combat viral, bacterial and parasitic infection.