Small molecules used to block proteins in HIV

WEST LAFAYETTE, Ind. -- Taking a cue from the Biblical story of David and Goliath, Purdue University scientists are using small molecules to bring down the molecular giants responsible for viral replication in AIDS.

The new approach blocks the interaction of two identical proteins that make up HIV protease by strategically slinging small molecules between key segments on the proteins as they come together to form an enzyme needed for viral replication. HIV protease is one of three essential enzymes used by the AIDS virus to replicate.

By targeting the site where the proteins come together, the small molecules can serve as a "molecular wedge" to prevent the proteins from interacting, thus thwarting the chain of chemical reactions needed to replicate, says Jean Chmielewski (she-ma-LEW-ski), associate professor of chemistry at Purdue who is a pioneer in the new approach.

"Theoretically, if you can stop the proteins from coming together and performing their biological activity, you'll stop viral replication," she says.

The method is currently being tested at the National Institutes of Health in cells infected with HIV, the virus that causes AIDS. If the studies prove successful, the general approach may someday be used to treat a wide range of diseases and disorders, including some currently untreatable conditions such as autoimmune diseases.

"At this stage, we've been able to synthesize some fairly potent small-molecule inhibitors of HIV protease, which do, in fact, block the ability of this enzyme to come together," Chmielewski says. "That, in turn, blocks its biological activity."

Chmielewski will present details of the new method Sunday (8/20) at the American Chemical Society's national meeting in Washington, D.C.

The new approach is based on the fact that an individual protein usually must work in conjunction with other proteins to carry out vital functions within a cell.

"There are a lot of disease states that are perpetuated b

Contact: Susan Gaidos
Purdue University

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