Eda Canales, Winston C. Tse, Scott D. Schroeder, Chien‐Hung Chou, Qi Liu, Jennifer Zhang, Scott E. Lazerwith, Philip Morganelli, Roland D. Saito, Gediminas Brizgys, Jiayao Li, Qiaoyin Wu, Michael Graupe, Randall L. Halcomb, Manoj C. Desai, Carina Cannizzaro, Eric Hu, Jason K. Perry, Armando G. Villaseñor, John R. Somoza, Ryan Ferrao, S. Swaminathan, Jim Zheng, Bing Lu, Judy Mwangi, Kelly Wang, Raju Subramanian, Bill J. Smith, Gerry Rhodes, William Rowe, Dorothea Sauer, Latesh Lad, Giuseppe A. Papalia, Sheila Clancy, George Stepan, Helen Yu, Roman Sakowicz, Bing Shi, Gavin Carr, Rujuta A. Bam, Luong Tsai, Eric A. Singer, Derek Hansen, Andrew Mulato, Stephen R. Yant, Tomáš Cihlář, John O. Link
Abstract The HIV capsid is essential to the virus lifecycle, making it a promising target for therapeutic intervention. In 2006, a screening campaign was initiated to identify small molecules capable of disrupting the protein–protein interactions required for self-assembly of the 1500 capsid monomers that form the 37 MDa fullerene cone-shaped capsid. Numerous compound design cycles over many years were undertaken to discover the complex structural elements that together afford the multistage HIV capsid inhibitor lenacapavir. Lenacapavir is the most potent (HIV-1 EC50 = 105 pM) and longest-acting HIV antiviral to date, with a unique twice-yearly dosing regimen. Clinically, lenacapavir has demonstrated robust efficacy for both HIV-1 treatment and prevention, and, remarkably, achieved 100% protection in women for the first time. These findings represent a significant advancement in treatment and prevention of HIV-1 infection, offering the potential to profoundly impact the global course of the HIV epidemic.