The HIV virus uses a protease to process its proteins following synthesis in the host cell. Inhibition of this process can prevent replication of the virus. Several inhibitors have been used clinically, but development of resistance is an ongoing problem. I have collaborated with Prof. Arun Ghosh of Purdue University on the development of new inhibitors that are effective against many drug resistant strains of the HIV-1 virus. One of these inhibitors, Darunavir, was recently approved by the FDA.
The inhibitor darunavir was crystallized in the active site of HIV-1 protease (J. Mol. Biol. 338:341-352, 2004), Protein Data Bank entry 1S6G). This inhibitor can hydrogen bond to the water molecule which is bound to Ile 50A and Ile 50B at the top of the active site. It has a hydroxy group which can hydrogen bond to the two active site aspartic acids, Asp 25A and Asp 25B. It can also hydrogen bond to the backbone NH hydrogens of Asp 29A, Asp 30A, and Asp 30B and to the backbone C=O of Gly 27A . The extensive hydrogen bonding to the backbone of the protein make this inhibitor active against numerous drug-resistant mutants; proteins tend to maintain backbone conformation even when side chains are mutated.
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