Inhibitors of the HIV-1 capsid, a target of opportunity.

Purpose Of Review: To summarize recent advances in the discovery of chemical inhibitors targeting the HIV capsid and research on their mechanisms of action.

Recent Findings: HIV infection is critically dependent on functions of the viral capsid. Numerous studies have reported the identification of a variety of compounds that bind to the capsid protein; some of these inhibit reverse transcription and nuclear entry, steps required for infection. Other capsid-targeting compounds appear to act by perturbing capsid assembly, resulting in noninfectious progeny virions. Inhibitors may bind to several different positions on the capsid protein, including sites in both protein domains. However, the antiviral activity of many reported capsid-targeting inhibitors has not been definitively linked to capsid binding. Until recently, the low-to-moderate potency of reported capsid-targeting inhibitors has precluded their further clinical development. In 2017, GS-CA1, a highly potent capsid inhibitor, was described that holds promise for clinical development.

Summary: Small molecules that bind to the viral capsid protein can be potent inhibitors of HIV infection. Capsid-targeting drugs are predicted to exhibit high barriers to viral resistance, and ongoing work in this area is contributing to an understanding of the molecular biology of HIV uncoating and maturation.