HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Abstract

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.

Author Summary

Although the current standard of care for Human Immunodeficiency Virus (HIV) is high, viral resistance has emerged to every drug currently in the clinic, in some cases rendering the entire class ineffective for patients. A new class of antiretroviral drugs would be effective against strains of HIV-1 that are resistant to any existing drug and would expand the therapeutic options available to patients. Capsid is the primary structural protein of HIV and a critical part of the viral replication cycle, both in the assembly of viral particles and in the infection of host cells. We report a new class of antiretrovirals that targets HIV-1 capsid and demonstrate that it is active at two critical stages in the viral replication cycle. These compounds were consistently effective against a range of clinical strains of HIV-1, from various sub-types, as well as HIV-2. Finally, the compounds bind in a unique pocket on capsid that has not previously been highlighted as a drug binding site. We believe this new class of antiretrovirals can serve as a starting point for the development of a new generation of HIV-1 therapeutics and, more generally, underscores the potential of capsid as a therapeutic target.