Surprising Keys to a New Anti-HIV Compound

Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.

January 15, 2010—Combination antiretroviral therapy, known as HAART, has dramatically increased the life expectancy of people with HIV/AIDS. Our ability to control the growth of HIV and block its attack on immune cells is based on having a large repertoire of drugs belonging to different drug classes. There are currently six different classes of antiretrovirals, each of which slows the life cycle of the virus at different stages of its growth. And within a single class, different drugs may have different potencies, resistance patterns, and side effects.

Now Dr. Bruno Marchand of the University of Missouri, recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research, reports on the mechanism of action of a new type of reverse transcriptase (RT) inhibitor, which holds great potential for development as a novel anti-HIV drug.

RT inhibitors have a long history and were the first medications approved by the Food and Drug Administration to treat HIV infection. Since the first of these—AZT—was developed, scientists have sought ways to improve the potency of drugs belonging to this class, while simultaneously minimizing their side effects. Writing in the December 2009 issue of the Journal of Biological Chemistry, Dr. Marchand—together with colleagues at Kyoto and Kumamoto universities in Japan, the University of Pittsburgh, the National Institutes of Health, and a Japanese pharmaceutical company—characterizes a new RT inhibitor known as EFdA. It is closely related chemically to the nucleoside RT inhibitors that were the first FDA-approved anti-HIV medications. But EFdA has two key differences: markedly increased potency compared to its chemical cousins, and unique specifics as to its mechanism of action.

The hallmark of all seven of the other closely related anti-HIV drugs is lack of a chemical structure known as 3'-OH, a molecule consisting of oxygen and hydrogen that occurs naturally on the DNA building blocks these drugs are designed to mimic. In fact, until the work of Marchand and colleagues, most scientists believed that the absence of 3'-OH was critical to the activity of all RT inhibitors, even though its absence has other detrimental effects on drug activity. But EFdA does have 3'-OH. EFdA is also more readily trapped within cells, where it can attack HIV, due to its ability to undergo a chemical reaction within cells known as phosphorylation. This process converts the DNA building blocks into a mature form that more effectively prevents the emergence of the virus.

Weight for weight, EFdA was almost 500 times more potent than AZT at killing HIV in the test tube. As such, given that it has the 3'-OH structure, it is unique among RT inhibitors that others have developed. For example, entecavir, an RT inhibitor that also contains 3'-OH, is a strong inhibitor of hepatitis B virus but acts only weakly against HIV. Marchand and colleagues concluded, “By understanding the molecular details of RT inhibition by [EFdA], we hope to gain insights into the design of more efficacious inhibitors.”

Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is vice president and director of research.