After 20 years of research, British and US investigators have solved the puzzle of creating a working model of integrase, opening the way for better AIDS treatments. Integrase, an enzyme produced by retroviruses enabling them to integrate linear viral DNA into a host cell chromosome, is necessary for HIV replication.
Though integrase inhibitor drugs can block this copying process, their mechanism of action remained speculative, noted Peter Cherepanov, of Imperial College-London, and colleagues from Harvard University. The researchers have grown a crystal that enables them to see the structure of full-length retroviral integrase. With such a model, researchers can begin to understand how integrase inhibitors work, possibly improving them and preventing HIV from becoming drug-resistant.
"When we started out, we knew that the project was very difficult, and that many tricks had already been tried and given up by others long ago," said Cherepanov. "Therefore, we went back to square one and started by looking for a better model of HIV integrase which could be more amenable for crystallization."
The crystal grown used a version of integrase borrowed from another retrovirus. It took the team more than 40,000 tries to generate a crystal of sufficiently high quality for a view of integrase's three-dimensional structure. In testing integrase inhibitor drugs on the crystals, Merck & Co.'s Isentress and the experimental Gilead Sciences product elvitegravir, the researchers were able to see for the first time how the inhibitors bind to and block integrase.
The full report, "Retroviral Intasome Assembly and Inhibition of DNA Strand Transfer," was published online by Nature (2010;doi:10.1038/nature08784).
02/01/10
UNITED KINGDOM: Scientists Solve HIV/AIDS Puzzle for Drugs
Source: Reuters:: Kate Kelland; Courtesy of the CDC National Center for HIV, STD, and TB Prevention