Special Report on Drug Resistance

New class of inhibitor may attack resistance

Potential drug could be cost-efficient

There is new hope for a cost-efficient treatment for HIV-1 infected patients who no longer respond to protease inhibitor (PI) treatment due to multidrug resistance.1

Investigators in a collaboration involving Wayne State University in Detroit, Stanford (CA) University, and Northwestern University in Evanston, IL, are working on creating a new class of inhibitor that would work most effectively with patients who have been on PI therapy and have developed multidrug resistance to the currently available PIs, says Ladislau Kovari, PhD, an associate professor of biochemistry and molecular biology at Wayne State.

"These new protease inhibitors would be too large to be useful in treating treatment-naïve patients," he says. "But they are specifically targeted for the patients who have already developed resistance to currently available protease."

Investigators are exploring collaborations with pharmaceutical companies, Kovari says.

Viruses with certain mutations can survive in the presence of drugs, but they lose fitness and cannot replicate as well, and so they do not exert as great of a negative pressure on the immune system, says Rodger MacArthur, MD, an associate professor of medicine in the division of infectious diseases and director of HIV/AIDS clinical research at Wayne State.

"So an individual with HIV might be able to live longer and do better clinically if the person has a resistant virus than if the person had a virus that is not resistant to the drug," he says. "The good news about resistance is that while we’re not saying we want to encourage resistance, we may be able to get patients stabilized for years."

The trick is to get the mutation to work to the patient’s advantage, and an inhibitor that is designed specifically to treat a mutated virus might be the way to do this, MacArthur explains.

The new class of inhibitor would work this way: "Imagine the protease inhibitor as the key, and the Y-type protease in treatment-naïve patients as the lock," Kovari says. "What we’re finding is the lock is expanding as the virus mutates, so the key, the inhibitor, doesn’t bind tightly to the multidrug-resistant protease."

Based on this understanding, researchers are designing an inhibitor that is larger and will fit in the expanded lock, he adds.

"We’re currently at the stage where we know what to design, and we have just started to design these larger drugs," Kovari says. "So the next step is to test these larger drugs in the laboratory, and then once we have laboratory data, we can take these inhibitors into clinical development and test them in patients."

If this new class of inhibitors succeeds, the good news is it will involve expanded analogs of currently licensed inhibitors, which likely would have similar properties in terms of side effects, he says.

"We are not building from scratch," Kovari explains. "We’re building based on clinical and licensed experience of current inhibitors, so these inhibitors will be similar, except larger, and they can be ingested orally."

For these reasons, it’s likely the new class of inhibitor would be less costly to develop and, therefore, cheaper to bring to market, he notes.

"To my knowledge, this approach is novel," Kovari says. "We are looking at atomic detail as changes of virus, and based on that structural understanding, we are adapting the inhibitors to restore efficacy."

Reference

1. Martinez JL, MacArthur R, Vickrey J, et al. The multidrug-resistant HIV-1 protease represents a novel drug target. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; November 2004. Poster H-209.