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A Poke In The Eye: Inhibiting HIV-1

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Researchers have developed what they believe is the first new mechanism in nearly 20 years for inhibiting a common target used to treat all HIV patients, which could eventually lead to a new class of AIDS drugs.

Image of the molecule researchers discovered that keeps the flaps from closing on the HIV-1 protease. It inhibits the flaps from closing, and prevents the protease from assembling an active virus. (Credit: Kelly Damm)

Researchers at the University of Michigan used computer models to develop the inhibiting compound, and then confirmed in the lab that the compound does indeed inhibit HIV protease, which is an established target for AIDS treatment. The protease is necessary to replicate the virus, says Heather Carlson, U-M professor of medicinal chemistry and principal investigator of the study.

Carlson stresses this is a preliminary step, but still significant.

“It’s very easy to make an inhibitor, (but) it’s very hard to make a drug,” said Carlson, who also has an appointment in chemistry. “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.”

What’s so exciting is how differently that mechanism works from the current drugs used to keep the HIV from maturing and replicating, she says. Current drugs called protease inhibitors work by debilitating the HIV-1 protease. This does the same, but in a different way, Carlson says.

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 center 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. Scientists knew the flaps opened and closed, but didn’t know how to target that as a mechanism, Carlson says.

Carlson’s group discovered 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.

In addition to a new class of drugs, the compound is key because 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,” Carlson said. “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.”

Kelly Damm, a former student and now at Johnson & Johnson, initially had the idea to target the flaps in this new way, Carlson says.

“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,” she said. “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.”

Kelly L. Damm, Peter M. U. Ung, Jerome J. Quintero, Jason E. Gestwicki, Heather A. Carlson.

A poke in the eye: Inhibiting HIV-1 protease through its flap-recognition pocket.

Biopolymers. Volume 89, Issue 8 , Pages 643 – doi: 652.10.1002/bip.20993

A novel mechanism of inhibiting HIV-1 protease (HIVp) is presented. Using computational solvent mapping to identify complementary interactions and the Multiple Protein Structure method to incorporate protein flexibility, we generated a receptor-based pharmacophore model of the flexible flap region of the semiopen, apo state of HIVp. Complementary interactions were consistently observed at the base of the flap, only within a cleft with a specific structural role. In the closed, bound state of HIVp, each flap tip docks against the opposite monomer, occupying this cleft. This flap-recognition site is filled by the protein and cannot be identified using traditional approaches based on bound, closed structures. Virtual screening and dynamics simulations show how small molecules can be identified to complement this cleft. Subsequent experimental testing confirms inhibitory activity of this new class of inhibitor. This may be the first new inhibitor class for HIVp since dimerization inhibitors were introduced 17 years ago. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 643-652, 2008.


Written by huehueteotl

May 20, 2008 at 7:29 am

Posted in HIV

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