Design, Synthesis, Evaluation, and Crystallographic-Based Structural Studies of HIV-1 Protease Inhibitors with Reduced Response to the V82A Mutation

In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C₂-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1′. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of the Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.