New Insights into Old HIV Drug Classes: Uncovering Novel HIV Inhibitors

By Jeffrey Laurence, M.D.

Dr. Bruno Marchand

June 9, 2010— Our ability to suppress the growth of HIV—potentially for the lifetime of an infected individual—is based upon a large repertoire of anti-HIV drugs, each of which employs a different mechanism of action. Working together in combinations known as highly active antiretroviral therapy (HAART), these inhibitors of key HIV proteins, such as reverse transcriptase (RT), protease, and integrase, act powerfully against HIV and reduce the patient’s chance of developing drug resistance.

In 2009, Dr. Bruno Marchand, recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research, described a new type of RT inhibitor with great potential as an anti-HIV drug. Now, writing in the May 2010 issue of the scientific journal BBA, Marchand, from the University of Missouri, together with colleagues at McGill University and the National Cancer Institute, reviews methods of discovering additional novel drugs within the RT inhibitor class.

Dr. Marchand notes that current RT drug development technology is based upon molecular snapshots taken by X-raying crystals of RT. But these crystals are static; they don’t move in conjunction with an infected cell’s components. In real life, RT shifts and rolls in relationship to HIV’s genetic information—including its RNA and the DNA it helps make from that RNA—as well as in relation to the various host cell molecules to which it must bind in order to work. Marchand and associates point out that detailed pictures of those active events might illuminate new points at which RT could be stopped from working.

One new technique for obtaining those pictures is single molecule spectroscopy, or SMS. HIV RT is labeled with a “donor” material known as FRET, and the cell components with which RT interacts are tagged with an “acceptor” dye. When these components interact, the donor chemical meets up with the acceptor dye, giving off a fluorescent light. This signal can be tracked by SMS, capturing the movement of RT.

In their review, Dr. Marchand and associates provide specific examples of how SMS and related techniques revealed differences between drugs within two major classes of RT inhibitors, the nucleoside analogs such as AZT and the non-nucleosides, such as efavirenz. They conclude by recommending that scientists give special consideration to “HIV RT dynamics in future drug discovery and development efforts.” 

Dr. Laurence is amfAR’s senior scientific consultant.

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