HIV is a moving target, unpredictably changing direction to elude anti-AIDS drugs, but researchers at Rutgers are clearly on the track of solutions to combat HIV drug resistance.
Leading a multidisciplinary ensemble of colleagues, Rutgers Chemistry Professor Eddy Arnold recently reported on studies that revealed how some drugs may be getting the better of the virus' molecular defenses.
Reports in the May issues of Nature Structural & Molecular Biology and the Journal of Medicinal Chemistry propose answers to why it is relatively difficult for the AIDS virus to develop resistance to the drug, tenofovir, or the DAPY (diarylpyrimidine) family of compounds, and offers explanations of the mechanisms involved.
Tenofovir and the DAPY compounds are different types of reverse transcriptase (RT) inhibitors. RT is the enzyme or molecular machine the AIDS virus uses to replicate its genetic material. The two life-saving drugs approach the problem of drug resistance in different ways.
Arnold and his colleagues work on drugs that target HIV RT. "We try to understand how these drugs work and how they may be able to evade resistance mechanisms so that we can apply the information to the design of better drugs," said Arnold, a resident faculty member of the Center for Advanced Biotechnology and Medicine. The research institute is jointly administered by the University of Medicine and Dentistry of New Jersey and Rutgers, The State University of New Jersey.
Since 1987, Arnold has collaborated with Stephen Hughes of the National Cancer Institute's Cancer Research and Development Center at Frederick, Md., constituting what Arnold calls "an inseparable team." Hughes is providing the biochemical analysis of the problem in conjunction with Arnold's X-ray crystallography – a method by which X-ray diffraction patterns obtained from crystals are used to map the three-dimensional atomic structure of large molecules.
"We have been fighting this battle together for more than 15 years," said Hughes. "We are both very excited about developing a better understanding of the fundamental biology of HIV and, even though it is a deadly enemy, we can't help admire its cleverness. We are making good progress, but the battle is far from over."
HIV RT uses ingredients available within the cell as building blocks to make the genetic copies that allow the virus to proliferate. These building blocks or substrates are fitted together to create new copies of the viral genetic information.
Arnold's team, including scientists from Gilead Sciences and the National Institutes of Health (NIH) as well as Rutgers Chemistry Professor Roger Jones, conclude that tenofovir – on the market for two years as Viread from Gilead Sciences – is relatively effective in evading HIV resistance because it's "lean and mean."
The tenofovir molecule is slightly smaller than the normal building blocks, which enables it to substitute for those the RT is trying to use. Because tenofovir is smaller, it is difficult for RT to learn to distinguish it from the normal building blocks and develop resistance to the drug. The interpretation provides insight into one mechanism of drug resistance, but the researchers also explored another mechanism displayed by the DAPY family of compounds.