(719f) The Broad-Spectrum Mechanisms and Design of Capsid Inhibitors for HIV-1

The risk of drug resistance during antiretroviral treatment of human immunodeficiency virus type 1 (HIV-1) has motivated the search for drugs based on novel mechanisms of action. One promising target is capsid (CA), a highly-conserved (>70%) viral protein; within viral particles, thousands of CA collectively self-assemble into the “mature” conical shell that is essential to protect and smuggle viral materials into new cells. Capsid inhibitors (CIs), such as PF-3450074 (Pfizer) and GS-CA1 (Gilead Sciences), have been shown to exhibit effects at multiple stages of the viral lifecycle while remaining effective at concentrations in the pM to nM regimes. In this work, we develop coarse-grained (CG) models and use molecular dynamics simulations to first elucidate the mechanisms that enable these CIs to have such curious broad-spectrum activity. Our analysis show that CIs have a profound impact on the hierarchical self-assembly of CA through the emergence of alternative assembly pathways with increased structural pleomorphism of mature cores. Two relevant phenotypes are observed: (1) eccentric capsid formation that may fail to encase the viral genome and (2) rapid disassembly of the capsid, which express at late and early stages of infection, respectively. We next investigate the possible design space of oligomeric targets for CIs and quantify the relationship between oligomeric structure and the population of non-infectious states. On the basis of this analysis, we discuss principles for the design of effective CIs. Finally, our study emphasizes the importance of adopting a dynamical perspective on inhibitory mechanisms and provides a basis for the development of future therapeutics that are effective at low stoichiometric ratios of drug to protein.