Crystal structures of trimeric HIV Env with entry inhibitors BMS-378806 and BMS-626529

The HIV-1-envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4-bound, CCR5-bound) and postfusion states to facilitate HIV-1 entry. Although the prefusion-closed conformation is a potential target for inhibition, development of small molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of HIV-1-Env trimer with BMS-378806 and its derivative, BMS-626529, for which a prodrug version is currently in Phase III-clinical trials. Both lead candidates recognized an induced-binding pocket, which was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20-21-hairpin. In both structures, the β20-21-region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms whereby these small-molecule leads inhibit CD4–induced structural changes in Env.