McGill University researchers have discovered how the antiviral agent foscarnet inhibits HIV replication, laying the groundwork for the development of similar but less toxic drugs. Their findings have been published in the February issue of the Journal of Biological Chemistry.
Foscarnet, an inhibitor that blocks the reverse transcriptase (RT) enzyme and counteracts resistance to common anti-HIV drugs such as AZT, is sometimes used in patients with multiple drug-resistant HIV-1 when no other treatment options are available. However, its clinical practicality is severely limited by the risk of serious side effects, including diabetes, kidney toxicity, irregular heartbeat, nausea, fever and rash.
Dr. Matthias Götte, a researcher and assistant professor in the Department of Microbiology and Immunology at McGill, and PhD students Bruno Marchand and Egor Tchesnokov are the first to show that the HIV-1 RT enzyme oscillates between active and inactive forms and that foscarnet freezes the enzyme in its inactive state. Binding of the inhibitor to this form of the enzyme reduces its resistance to AZT.
"Nobody knew that these oscillations existed in HIV-1 RT," said Dr. Götte. "The question is, now that we understand the mechanism, can we translate this into the development of new foscarnet-like molecules?"
The study, funded by a three-year, $255,000 grant from the Canadian Institutes of Health Research (CIHR), complements research published last year in the Journal of Virology, in which Götte and researchers from the Belgian pharmaceutical company Tibotec discovered novel anti-HIV compounds that likewise affect the natural oscillation of the RT enzyme.
"Both papers validate new target sites in HIV-1 RT enzymes," said Dr. Götte, "so the combined findings may provide the basis to develop novel, perhaps less toxic and more potent inhibitors that block the replication of drug-resistant HIV variants."