NEW BRUNSWICK/PISCATAWAY, N.J. – 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.
Arnold and coworkers have worked extensively with the DAPY compounds, the subject of the second report. For more than a decade the late Paul Janssen, founder of Janssen Pharmaceutica, led an international research effort developing these drugs. The team includes medicinal chemists, virologists, molecular modelers, and crystallographers from Rutgers and the NIH in the United States, as well as from Johnson & Johnson subsidiaries, Janssen Pharmaceutica in the United States and Belgium, and Tibotec-Virco, N.V. in Belgium.
Several of the DAPY compounds have shown unprecedented results in early stage clinical trials. The compounds TMC-120 (dapivirine) and TMC-125 (etravirine), when given as single agents, performed as well as three- and five-drug combinations, the standard for anti-HIV therapy. Janssen, the driving force behind the discovery of these drugs, also had developed 77 other drugs for the treatment of a wide range of diseases.
The DAPY compounds attach themselves to a site near the heart of the RT molecular machine and block its activity. "It's like throwing a molecular monkey wrench into the virus's essential machinery," Arnold said. The success of the compounds may be due to their ability to assume different shapes, allowing them to adapt to the changing shapes found in the virus's repertoire of drug-resistant forms. Arnold describes the DAPY antics as "rolling with the punches, wiggling and jiggling around until they fit the particular RT configuration."
"The conclusions we have drawn do not represent an endpoint, but rather punctuation marks – places where we have achieved some significant milestones that will help guide us in the design of new and more effective anti-AIDS drugs," Arnold said.
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