New Drugs to Combat AIDS
4 May, 2007 12:40 pm
AIDS remains an important health problem worldwide. Much cheaper drugs are needed to combat AIDS and HIV infection in developing countries. Drug companies are also searching for anti-HIV drugs that work in new ways.
Pharmaceutical companies have now developed many drugs for combination therapy. Each drug generally targets one of two HIV enzymes, reverse transcriptase or HIV protease. Action of these enzymes is blocked by the drug, preventing infected cells from making new virus. HIV levels in the body drop drastically, but the virus is not eradicated and infected cells are never “cured”. There are now so many of these drugs on the market that companies are seeking new types of anti-HIV drugs in order to gain a competitive edge.
One promising type of new anti-HIV drug is called an “entry inhibitor”. These drugs are particularly attractive because they prevent HIV from entering cells, which never become infected. In order to enter the target host cell, “receptor molecules’ on the surface of the virus and on the host cell must first bind together. The “handshake” enables the membranes of the virus and host cell to fuse and the contents of the virus to enter the cell. A number of experimental drugs are being studied that bind either the HIV receptor (gp120), or the principal receptor on the host cell (CD4), or co-receptors on the host cell that also play a role in membrane fusion. Drugs that bind these receptors block the handshake needed for entry of the virus into the host cell.
Last year, the full chemical details of a new type of HIV entry inhibitor were published in the Journal of Medicinal Chemistry (2006, 49, 1291-1312). On the AIDS/HIV research portal aidshivresearch.com, this article was the top 90th out of more than 10,000 for 2006. The results are the culmination of almost two decades of research. The story begins at the State University of New York at Stony Brook, where graduate student Heung-Jin Choi made a compound later called “CADA”. Working with Professor Thomas Bell, Dr. Choi, now a chemistry professor in Korea, made CADA in an attempt to develop a compound for binding the metal lithium. After Dr. Choi completed his Ph.D. in 1989, CADA and many other compounds from the Bell research group were sent to the National Institutes of Health to be screened for anti-HIV activity. CADA was found to prevent HIV replication in cells and became a new lead for anti-HIV drug development.
Over the intervening years, the Bell research group at Stony Brook, and after 1995 at the University of Nevada, Reno (UNR), made a large number of CADA analogues. These analogues have slightly different molecular structures and many are described in the J. Med. Chem. article. These compounds were synthesized to identify what parts of the CADA molecule are important for anti-HIV activity and to discover more potent and more soluble drugs. More potent drugs could be used in smaller amounts, potentially with less risk of side effects, and more soluble CADA analogues might be administered to patients orally, in pill form.
In 2000, the Bell research group began working with scientists at the Rega Institute for Medical Research in Belgium, including Prof. Dominique Schols and Dr. Kurt Vermeire. Schols and Vermeire discovered that CADA inhibits HIV replication by greatly decreasing the amount of CD4 receptor on the host cell. This takes away the “door handle” needed by the virus to enter the cell. This mechanism is exciting, because it may be possible to use CADA compounds for HIV prophylaxis. That is, someone at risk of HIV exposure could use the drug to prevent HIV infection.
The exact way in which CADA decreases CD4 on host cells is not known and is currently being investigated by Bell and his collaborators. Working with Prof. William Welch of the biochemistry department at UNR, the Bell group has developed a computer-based method for predicting the potencies of new CADA analogues; this is also reported in the J. Med. Chem. article. The group is continuing the synthesis of new CADA analogues using this computer model. Another current objective is to make CADA “prodrugs” that are soluble enough for oral administration but are changed into active molecules by enzyme action in the body.
So far, CADA compounds are experimental drugs and very few studies have been done in animals. Hence, they are still at least a few years away from being approved by the FDA for human use. Fortunately, a drug company is currently doing preliminary studies to investigate whether they can be developed into commercial drugs. Promising signs are that many have low toxicity and can be made relatively inexpensively. They also may offer a great advantage over conventional anti-HIV drugs: they may not be susceptible to viral resistance. This is because it is believed that virulent strains of HIV cannot use any receptor other than CD4 to enter the host cell.
CADA’s effects are specific for CD4; no other cell-surface molecule has been found to be affected by the drug. CD4 is not believed necessary for healthy function of the immune system, so adverse effects are not expected. Moreover, CD4 is involved in certain autoimmune conditions, such as rheumatoid arthritis. Hence, CADA analogs may be useful not only as AIDS drugs, but also for treatment of autoimmune disorders.
Thomas Bell et al. Journal of Medicinal Chemistry (2006, 49, 1291-1312)