The treatment of HIV/AIDS remains a challenge. Despite 30 years of breakthroughs, a cure remains elusive. Integrating ideas and methods from structural biology, enzymology, medicinal chemistry, protein engineering, and virology has led us to several novel strategies directed at the HIV-1 protease. We have solved the first crystal structure of the HIV-1 protease in a complex with a substrate optimized by phage display. Our structure reveals unprecedented side-chain hydrogen-bonding interactions. By analyzing this and other co-crystal structures, we have discovered an unappreciated stereoelectronic effect (namely, an n-to-pi* interaction) within the substrate that has important implications for both the enzymatic reaction mechanism and drug design. We have also created a derivative of a clinical HIV-1 protease inhibitor with greatly enhanced potency. By considering co-crystal structures, we have enabled darunavir to form additional hydrogen bonds with the enzymic S2’ subsite. The key is replacing the aniline moiety of darunavir with a phenylboronic acid. The new ligand has a 20-fold greater affinity for the wild-type protease than does darunavir and maintains high affinity for a protease variant with a drug-resistance substitution in the S2’ subsite. Even the best protease inhibitors are susceptible to drug resistance. We have developed an alternative strategy that relies on the activity of the protease rather than on its inhibition. To do so, we used an intein to form a cyclic zymogen of an otherwise cytotoxic ribonuclease. Catalysis by HIV-1 protease restores wild-type activity, and emerging data suggest that our zymogen can be prophylactic for HIV-1 infection. These approaches could advance the treatment of HIV/AIDS and, potentially, other retroviral infections.

HIV protease as a target for novel antiretroviral therapies

256th National Meeting (2018)

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