Knowledge Bank

HIV-1 is the etiologic agent responsible for the progressive impairment of host immune function. While the introduction of combination antiretroviral therapies (cART) has dramatically reduced HIV-1-associated mortality, the emergence of drug-resistant viral strains necessitates the development of novel therapeutic modalities. The HIV-1 capsid protein (CA) is a highly attractive therapeutic target due to its essential, multifaceted role in both the early and late stages of the viral replication cycle. Small-molecule CA function inhibitors, such as PF74, exert their effect by disrupting CA's critical biological functions, thereby preventing viral replication. The objective of this research project is to rationally design and synthesize small-molecule HIV-1 CA-degraders utilizing PF74 as a lead compound. This was achieved by employing the recently reported targeted clearance strategy, AUtophagy TArgeting Chimeras (AUTACs), to induce selective degradation of the CA via the autophagy-lysosome pathway. Collectively, this project establishes a synthetic framework for developing novel CA degrading compounds and validates targeted CA degradation as a viable strategy in anti-HIV-1 drug design.