New AIDS Drug Discoveries To Battle Drug-Resistant HIV Strains

Two of the new drugs, Dapivirine (also called R147781 or TMC120) and R165335 (also called TMC125), are derived from the dianilinopyrimidine (DAPY) family of highly potent compounds. Both have shown great promise in Phase I and Phase II clinical trials.

Dapivirine, based on its ease of manufacture and low cost, is a viable candidate for treating AIDS in the developing world, home to 95 percent of all HIV-infected patients, the researchers said. It is also being tested as a microbicide to prevent the transmission of HIV.

A third compound (R278474), scheduled for Phase I trials, is even more active against common HIV strains and all the mutants tested, according to the researchers.

The team developing the drugs includes scientists from Rutgers, The State University of New Jersey, and the National Institutes of Health (NIH) in the United States; and from Janssen Pharmaceutica in the United States and Belgium and Tibotec-Virco, N.V. in Belgium, both subsidiaries of Johnson & Johnson.

In a presentation at the 224th American Chemical Society (ACS) national meeting in Boston (MEDI 206), Bart De Corte of Janssen Pharmaceutica described the drugs and Paul Lewi of the Center for Molecular Design (CMD) at Janssen Pharmaceutica in Belgium discussed the strategies used to design the drug molecules.

The research effort, which has been conducted under the overall guidance of Dr. Paul Janssen, began more than 10 years ago. Janssen, founder of Janssen Pharmaceutica, has been a leader in drug discovery and has developed drugs used to treat a wide variety of human diseases.

"A drug may be thought of as a key that fits a specific lock," said chemistry Professor Eddy Arnold, a Rutgers member of the team. "The appropriate drug or key should be able to disrupt the functioning of the AIDS virus without causing serious side effects for the patient. Drug-resistant variants may be seen as an array of locks that require different keys to prevent the spread of viral infection." Arnold, who is also a member of the Center for Advanced Biotechnology and Medicine (CABM) based at Rutgers and the University of Medicine and Dentistry of New Jersey, explained that an ideal drug needs to work like a "master key" that can fit into and block as many of the locks (HIV variants) as possible.

To reach the goal of a "master-key," chemists on the team first synthesized hundreds of molecules and used them to search for useful drug candidates. Computer calculations of the structures of the drug and the drug target (the key and the lock) helped predict the best molecules to synthesize. The resulting drug candidates were tested against drug-resistant HIV, leading the researchers to the DAPY family of compounds.

Arnold and his colleagues Kalyan Das and Art Clark at CABM and Rutgers' department of chemistry and chemical biology worked with Stephen Hughes and co-workers at the NIH National Cancer Institute in Frederick, Md., to produce images that showed exactly how the drugs bind to their HIV targets. This information was used to modify the drugs in ways to improve their ability to bind to HIV.

The design work was carried out at Janssen's Center for Molecular Design in Belgium. Using a supercomputer, researchers there compared millions of potential molecular designs in order to select candidates for chemical synthesis. Hundreds of these candidates were then synthesized at Janssen in the United States and then tested against drug-resistant strains at Tibotec/Virco. Two of the most promising drugs, Dapivirine and R165335, have been tested in Phase II clinical trials. When R165335 was given as a single drug, viral loads were reduced to a level comparable to that achieved with a five-drug combination.

The United States research team was guided by Arnold and Hughes, who began their collaborative studies of HIV in 1987 with the goal of facilitating more effective treatments for AIDS. Their work has been supported by funds from the NIH National Institutes for Allergy and Infectious Diseases, General Medical Sciences, and Cancer. Arnold's work has also been supported by Janssen Research Foundation.