Researchers at the University of Michigan used computer models to develop a new compound that can inhibit HIV protease, which is an established target for AIDS treatment and can further lead to a new class of AIDS drugs.
This is believed to be the first new mechanism in nearly 20 years for targeting HIV protease, which is needed by the virus for replication, said Heather Carlson, U-M professor of medicinal chemistry and principal investigator of the study. She also stressed that despite being a preliminary step, it is still significant.
"It's very easy to make an inhibitor, (but) it's very hard to make a drug. This compound is too weak to work in the human body. The key is to find more compounds that will work by the same mechanism," said Carlson.
She indicated that most importantly, this mechanism works quite differently from the current drugs, called protease inhibitors, which work by debilitating the HIV-1 protease. This does the same, but in a different way.
A protease is an enzyme that clips apart proteins, and in the case of HIV drugs, when the HIV-1 protease is inhibited it cannot process the proteins required to assemble an active virus. In existing treatments, a larger molecule binds to the centre of the protease, freezing it closed.
The new mechanism targets a different area of the HIV-1 protease, called the flap recognition pocket, and actually holds the protease open. Though it was known that flaps opened and closed, but how to target that as a mechanism was unknown until now. It was also found that this flap, when held open by a very small molecule, half the size of the ones used in current drug treatments, also inhibits the protease.
Also, the compound is important as its smaller molecules have better drug-like properties and are absorbed much more easily.
"This new class of smaller molecules could have better drug properties (and) could get around current side effects. HIV dosing regimes are really difficult. You have to take medicine several times in the day. Maybe you wouldn't have to do that with these smaller molecules because they would be absorbed differently," said Carlson.
Carlson said that it was Kelly Damm, a former student and now at Johnson and Johnson, who initially had the idea to target the flaps in this new way.
"In a way, this works like a door jam. If you looked only at the door when it's shut, you'd not know you could put a jam in it. We saw a spot where we could block the closing event, but because everyone else was working with the closed form, they couldn't see it," she said.