PHYS 11 |
| Drug-resistance occurs when mutations in the target protein allow the protein to retain function while no longer being inhibited efficiently by the drug. In HIV-1 protease drug-resistance occurs when the enzyme is able to retain the ability to cleave the Gag and GagProPol polyproteins at ten sites and allow viral maturation even in the presence of protease inhibitors effectively rendering current therapies ineffective. All of the substrates recognized by HIV protease appear to adopt a particular shape or “substrate envelope”. Many of the drug resistant mutations that occur in HIV protease occur in regions that do not directly contact the substrate envelope. Thus, drug resistance occurs at locations that are least likely to impact substrate recognition. Through collaboration we have used this insight to design, synthesize, assay and analyze novel tight binding HIV-1 protease inhibitors. These inhibitors successfully bind a series of drug resistant proteases without loosing affinity. |
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Structural Determination, Refinement, and Modeling of Large Biomolecular Complexes
8:00 AM-12:00 PM, Sunday, August 19, 2007 BCEC -- 157C, Oral
Division of Physical Chemistry |