amfAR, The Foundation for AIDS Research

Designer Drugs For HIV

By Jeffrey Laurence, M.D.


October 17, 2006—The persistence of drug-resistant HIV strains acquired at the time of initial infection is of growing concern, and overcoming and avoiding drug resistance is critical to successfully treating HIV disease and thus prolonging life.

Extensive resistance to the three major classes of HIV drugs—protease inhibitors (PI), nucleoside and nucleotide reverse transcriptase inhibitors (NRTI) such as AZT and tenofovir, and the non-nucleoside RTIs (NNRTI) such as efavirenz—ranges from 4 to 15 percent in the U.S. Such high degrees of resistance are linked to poorer survival. This has led AIDS physicians to argue for drug resistance testing of all HIV-positive people before they start taking antiretroviral drugs, similar to the way resistance testing is seen as the "standard of care" to guide treatment decisions for patients on a failing antiretroviral regimen.

The major drugs involved in clinically relevant HIV resistance are the NRTIs and NNRTIs. Protease inhibitors contribute much less to overall drug resistance, which may relate to the marked increase in use of so-called boosted PI regimens. They provide a strong barrier to resistance development and may be more tolerant of less than perfect medication adherence. But a growing number of patients have exhausted the current arsenal of anti-HIV drugs, and persistent viral replication with few treatment options eventually leads to disease progression and death.

In September two amfAR grantees published articles on new and very different ways of attacking HIV-associated drug resistance.

Dr. Antonin Holy of the Institute of Organic Chemistry and Biochemistry in Prague, Czech Republic, writing in the journal Antiviral Research, reviews the work of his group and others on the modification of NRTI-like drugs, opening their closed ring structures, adding on chemical groups to alter their electric charge and increase their ability to enter cells, and so on. Some drugs they have altered in this manner already show better blood levels than the classic parent compounds, as well as greater anti-viral potency, not only against HIV, but hepatitis B and other DNA-containing viruses as well.

Dr. Thomas L. James from the Chemistry and Chemical Biology Group at the University of California, San Francisco, writing in the journal Chemistry & Biology, took an entirely different approach. His group is working on a new class of anti-HIV agents, targeting neither the two viral enzymes for which FDA-approved drugs now exist (reverse transcriptase and protease), nor integrase, the promising third HIV enzyme target, nor viral fusion and entry. Instead his group sought to target a critical piece of viral genetic information known as TAR RNA. Building on an initial observation that derivatives of anti-depressant drugs, or phenothiazines, bind to TAR RNA, they used chemical and computer-based techniques to design molecules that best blocked the function of this RNA, forming a chemical "library" of potential drug candidates to explore.

amfAR has had a long history of seeking out and supporting such innovative research on new viral drug targets. The work of Drs. Holy and James provide the latest evidence of such forward-thinking ideas.

Dr. Laurence is amfAR’s Senior Scientific Consultant.