Structure of a benzosulfonamide based inhibitor 11l bound to a disulfide stabilised HIV-1 capsid hexamer

The Human Immunodeficiency Virus Type 1 (HIV-1) continues to be a major global health issue, with infection leading to Acquired Immunodeficiency Syndrome (AIDS). Despite advances in antiviral therapy, the need for new and more effective treatments remains critical. In this study, we determined the structure of the disulfide stabilised HIV-1 capsid protein hexamer in complex with the novel antiviral capsid inhibitor compound 11l. The structure revealed the presence of six 11l molecules bound to the capsid hexamer in a conserved site shared by nuclear import factors, and other capsid inhibitor compounds such as PF74 and GS-6207. The 11l compound exhibits disorder in the benzo-sulfonamide groups and disruption in the loop between helix 8 and 9 for the capsid C-terminal domain, an important 2-fold symmetry axis for hexamer formation. Our findings provide insights into the mechanism of action of 11l as a capsid inhibitor and antiviral. These results contribute to the ongoing efforts to develop more effective antiviral treatments for the global burden of HIV and AIDS. SynopsisInsight into the mechanism of action for a novel HIV-1 capsid inhibitor antivirals are elucidated by structure of HIV-1 capsid hexamer bound to the novel inhibitor compound 11l.