While highly active antiretroviral treatment (HAART) including inhibitors that target HIV-1 proteasea protein that allows viral maturation through cutting and releasing key viral components in the immature virushas been remarkably successful in decreasing mortality, the emergence of mutations of HIV-1 that are resistant to current drug regimens is a critical factor in the clinical failure of antiviral therapy. With this renewed funding, Schiffer and colleagues will continue to address this challenge with a comprehensive approach that integrates clinical data, structural biology and biophysical chemistry, medical informatics and biostatistics, biochemistry and molecular virology, computational chemistry and computer-aided design, and synthetic and medicinal chemistry. The integrated program embraces two overarching goals: to clarify the role of compensatory mutations in HIV-1 protease in conferring drug resistance and to develop new HIV-1 protease inhibitors that are more robust against drug resistance.
The occurrence of drug resistance negatively impacts the lives of millions of patients by limiting the longevity of many of our most promising new drugs. Through this integrated approach, we look forward to contributing to the development of drugs that promise to be more effective against HIV. Importantly, the new strategies we develop may also reduce drug resistance in other quickly evolving diseases, including lung cancer and hepatitis C, Schiffer said.
To date, Schiffer and collaborators have made a number of advances. In 2004, for example, they were able to determine the crystal structures of many of the substratesthe sites HIV-1 protease cuts in the immature virus allowing viral maturationand to compare their shape with the existing drugs. They found that while the sequences of the sites that are cuts were different, they all fit within a similar space, which they dubbed the substrate envelope. Significantly, the investigators found
|Contact: Kelly Bishop|
University of Massachusetts Medical School