Combating Drug Resistance in HIV protease: A Structural ApproachHIV-1 protease is the target of the most potent anti-viral drugs for the treatment of HIV-1 infection. All ofthese drugs are the consequence of structure-based drug design. Unfortunately, many viable drug resistantvariants of HIV-1 protease have evolved under the selective pressure of drug therapy. To develop aneffective therapy, this ensemble of HIV-1 protease variants becomes the therapeutic target rather than onewild-type protease clone. Drug resistance at the molecular level is a subtle change in the balance ofrecognition events between the relative affinity of the enzyme to bind inhibitors and its ability to bind andcleave substrates. Mutations accumulate and confer drug resistance to HIV-1 protease in a complexinterdependent manner that maintains or accentuates viral fitness. At a molecular level these mutationsimpact inhibitor binding by changing the equilibrium between the unliganded and inhibited forms of protease.These changes can directly alter the active site cavity, such as those primary sites of resistance that occurwhere the inhibitors protrude from the substrate envelope. Alternatively, the changes can be indirect thatoccur outside the active site and may affect the flexibility or stability of the unliganded protease. In eithercase, the effects of mutations are often not additive; the impact of a mutation at one site influences the effectof a mutation at another site, in an interdependent fashion. In this proposal we will collaboratively pursue twooverall goals: (1) test the 'substrate envelope' hypothesis by designing, synthesizing and assaying novelHIV-1 protease inhibitors that fit within the substrate envelope and ascertain if they are more robust to drugresistant variants of HIV-1 protease (Tidor, Rana and Schiffer labs). (2) elucidate the role of known activeand non-active site mutations in conferring resistance to current and new protease inhibitors (Shafer,Swanstrom and Schiffer labs). Specifically our group collects and analyzes structural, thermodynamic anddynamic data to elucidate changes in variant proteases and in inhibitor recognition.
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