Analysis: AIDS pipeline bursting

SYDNEY, July 24 (UPI) -- Despite a current anti-AIDS arsenal of 28 drugs, researchers this week described several potential new compounds that attack the human immunodeficiency virus, the virus that cause AIDS.

"The pharmaceutical pipeline is loaded," Robert Murphy, professor of medicine at Northwestern University School of Medicine in Chicago, told United Press International.

Murphy, chairing a special session on the novel agents at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, said the drugs are going to be needed because HIV infection is incurable and requires lifelong treatment.

"We are no longer trying to keep people alive for just two, three or five years," said Robin Isaacs, executive director of infectious disease at Merck Research Laboratories in Upper Gwynedd, Pa. "We now need treatment options that will help patients live for 30 years or longer."

HIV is constantly mutating and eventually escapes the control of the current drugs, Isaacs told UPI. "We need more antiretroviral drugs to fight HIV infection because no matter how good we are the virus develops resistance as it evolves," he said.

In the session, Murphy said the research for now mainly involves compounds that have anti-HIV properties in the laboratory. "At this point, they are just compounds," he said. "Eventually we will be able to call them drugs, when they appear to be tolerable and effective in animals and humans."

Among the compounds and drugs discussed at the session, however, were some candidates that could be used experimentally in humans by the end of next year.

Karl Salzwedel, director of drug discovery for Panacos Pharmaceuticals Inc. in Gaithersburg, Md., said the company has three different groups of compounds that interrupt the ability of HIV to fuse to its target cells in the body.

"We expect to seek an IND (investigative new drug) application with the Food and Drug Administration by the end of this year, and we may begin clinical trials by the end of 2008," he told UPI.

These fusion inhibitors differ from enfuvirtide -- sold by Roche as Fuzeon -- now a mainstay among patients who have used numerous antiretroviral drugs against HIV in the past; it is injected twice a day. The Panacos compounds are designed to be orally bioavailable. They also work at different points in the cascade of molecular events that allows the virus to attach to and enter the cell.

Another Panacos drug, called by the catchy name of PA1050040, is a second-generation maturation inhibitor. These drugs work at the end stage of the HIV life cycle, preventing virus particles from reaching maturity and entering the bloodstream as infective material.

The first maturation inhibitor, bevirimat, is in phase 2B development by Panacos. The new molecule has a different resistance profile and is less likely to bind to protein than bevirimat. Phase 1 trials of PA1050040 are under way.

"It's encouraging to see this type of development," said Murphy. Even though no resistance to bevirimat has been seen in clinical trials, he said that the researchers are already working to overcome what most scientists who have been dealing with HIV believe will occur -- that resistance will arise.

Among the other research presented:

-- French chemists described a series of compounds called dihydroxytropolones that attack the reverse transcriptase enzyme, one of the three key enzymes of the HIV virus. Nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors all presently attack this facet of the HIV lifestyle.

-- A group of researchers from Ukraine have discovered small molecules that inhibit the ability of HIV tat-protein to activate cellular responses that play a critical role in progression of HIV infection. "We have always suggested that finding inhibitors of tat would be a welcome weapon in the AIDS arsenal," said Murphy.

-- Japanese researchers presented their early work in development of a molecule that prevents a critical process called dimerization in the protease enzyme, another of the critical enzymes of the virus. Numerous protease inhibitors are already marketed, but all appear susceptible to resistance. Murphy said the Japanese approach differs in its attack on the enzyme.

Isaacs, whose company was not involved in the research presented in the poster discussion session, said, "We have not yet reached the point where we have the perfect drug in the sense of tolerance and convenience." He said that development of an oral fusion inhibitor would answer the question of convenience for those taking enfuvirtide who require twice-a-day injections.

Murphy said most of the compounds discussed in the session "are a long way down the road, but these chemists that have developed the compounds are from very successful groups."