Effect of Flap Mutation I54L/M in Inhibition of Human Immunodeficiency Virus Type 1 Protease: Relationship to Drug Resistance

Human immunodeficiency virus type 1 (HIV-1) encodes a 22 kDa homodimeric aspartic protease that cleaves the gag and pol viral polyproteins at nine specific sites and thus permits viral maturation (Kohl et al., 1988). HIV-1 protease is one of the most extensively studied enzymes, both experimentally and computationally. Hence, the invention of drugs that restrict proteolytic processing by the protease is a prime goal in the treatment of HIV-1 infection. Nine commercially available drugs are based on the inhibition of this enzyme to treat acquired immune deficiency syndrome (AIDS) (Wensing et al., 2010). The clinical success of these drugs is hindered by the frequent occurrence of drug-resistant mutations of the HIV-1 protease. The resistant strains encode mutated proteases with reduced binding affinity for the inhibitors but with sufficient enzymatic activity to process the viral polyproteins. However, the emergence of active, drug-resistant mutants of the protease has limited the long-term effectiveness of these inhibitors. Thus, the design of HIV-1 protease inhibitors with novel mechanisms of action and reduced resistance liabilities is still desirable.