UNIVERSITY OF MASSACHUSETTS
As the AIDS pandemic continues, the emergence of HIV variants that are drug resistant is a therapeutic challenge. The nine FDA-approved HIV-1 protease inhibitors are currently the most potent of the anti-viral drugs in the treatment of HIV infected patients. All of these inhibitors were the results of structure based drug design. Yet variants of HIV protease have evolved which are resistant to one or more of these drugs. Even within a single patient an ensemble of different viruses and therefore proteases exist. The challenge for the community is to develop HIV-1 protease inhibitors that are robust and therefore less vulnerable to drug resistance. This is a multi-disciplinary challenge, as two key thrusts must be addressed - both the underlying mechanisms of resistance must be elucidated and new strategies for identifying robust inhibitors against resistance must be developed. This supplement accelerates one of the major goals of the 'parent' P01: Develop new HIV-1 protease inhibitors that are more robust against drug resistance. To date we have discovered ten HIV-1 protease inhibitors that are more potent than Darunavir, the best of the FDA approved HIV-1 protease inhibitors, against wild-type and resistant HIV-1 viruses. These inhibitors were developed with the use of the substrate envelope hypothesis, as a strategy to decrease the probability that drug resistance might occur. Additional HIV-1 protease inhibitors are currently being developed. In this supplement we are requesting funds to accelerate the development of these potent novel HI V-1 protease inhibitors by initiating preclinical tests. This development will help to stimulate the economy by providing resources to both academic and private United States of American institutions.