Researchers have discovered chemical compounds that could lead to HIV treatments that are 10 to 2,000 times more potent than drugs now on the market. “The current compounds or slight variants could become drugs,” says William L. Jorgensen, a professor at Yale University. The new agents work by inhibiting the function of an enzyme essential for HIV’s replication. That enzyme is called HIV-1 reverse transcriptase. Classed as non-nucleoside reverse transcriptase inhibitors, the compounds prevent HIV from converting its genetic material into DNA, a necessary step for the infection of human cells. Two of the new agents are extraordinarily potent against the predominant, “wild-type” form of HIV, which is highly adept at mutation, according to the researchers. “The compound that we call JLJ494 is, I believe, one of the most potent compounds ever reported for inhibiting replication of wild-type HIV,” Jorgensen says. These agents could allow for comparatively lower dosages, and also for prophylactic anti-HIV treatment, he says. Importantly, they also show very low toxicity towards human cells. “This discovery represents a giant leap forward in the design of more selective and less toxic AIDS drugs ” says pharmacology professor Karen S. Anderson. “We are excited about continuing the development of this new class of anti-HIV compounds.” A second, closely related compound, JLJ506, is also highly effective against wild-type HIV, as well as against two common mutant forms of the virus. The Jorgensen-Anderson team’s iterative approach, published in the Journal of Medicinal Chemistry, involved extensive computer modeling to design compounds that bind to the target enzyme. They then synthesized the most promising compounds and measured how they affected replication of the virus using live HIV and human T-cells. Yale has filed a patent application covering the compounds, and the scientific team continues to make new, related compounds. “We’re not done yet,” Jorgensen says. “There are many details in drug discovery.” Additional members of the team are from the departments of chemistry and pharmacology at Yale School of Medicine. The National Institutes of Health supported the research.