Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor Lenacapavir
S.M. Bester, Daniel Adu‐Ampratwum, Arun S. Annamalai, Guochao Wei, Lorenzo Briganti, Bridget C. Murphy, Reed Haney, James R. Fuchs, Mamuka Kvaratskhelia
Abstract
LEN is an investigational long-acting agent for future HIV-1 treatment regimens. While ongoing clinical trials have highlighted a largely beneficial profile of LEN for the treatment of HIV-1 infected people with limited therapy options, one notable shortcoming is a relatively low barrier of viral resistance to the inhibitor. Cell culture-based viral breakthrough assays identified N74D, Q67H, and N74D/Q67H capsid changes as the main resistance associated mutations (RAMs). N74D and Q67H capsid substitutions have also emerged in clinical trials in some patients who received subcutaneous LEN. Understanding the structural basis behind viral resistance to LEN is expected to aid in the rational development of improved inhibitors with enhanced barriers to resistance. Here, we report high resolution structures of the main drug resistant capsid variants, which provide mechanistic insight into the viral resistance to LEN. We used these findings to develop an improved inhibitor, which exhibited enhanced activity against the viral Q67H/N74D capsid phenotype compared with that of parental LEN.