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Harmless virus may hold key to more effective HIV drug discovery

August 29, 2005

New phage display technique successful in identifying compounds that show potential to overcome drug resistance

A simple, harmless virus might hold the key to the more effective and efficient development of HIV and anti-viral drugs, UCI chemical biologists have found.

In order to better identify compounds that can outmaneuver a virus' effort to mutate and multiply, Gregory Weiss and Allison Olszewski employed this virus, called a bacteriophage, to learn how a HIV protein could respond to a new class of anti-viral molecules they have discovered.

By constantly mutating into new variations, HIV, in particular, has been very skillful at developing resistance to broad-spectrum methods to inhibit its expansion. Because of this, the development of effective HIV drugs has been difficult and expensive.

Weiss and Olszewski found that the bacteriophage can model millions of different mutational variants of an HIV protein called Nef. Knowing how the entire population of Nef variants responds to new drugs gives researchers greater ability to identify broad-spectrum, anti-HIV compounds. This approach, Weiss said, can make drug discovery efforts for other anti-viral therapies faster and more effective.

Study results appear in online version of the Journal of the American Chemical Society.

"Viruses are clever about mutating to defeat the best efforts of chemists and biologists," said Weiss, an assistant professor of chemistry and molecular biology and biochemistry. "By recruiting a harmless virus, we're learning how HIV will respond to new classes of anti-viral drugs before these compounds are tested in the clinic, which is currently an expensive and time-consuming process."

The Weiss laboratory specializes in developing massive libraries of proteins that can potentially target and bind to other proteins, using a process called phage display. In this study, Weiss and Olszewski first created one such library by attaching the Nef protein onto the bacteriophage, which was then coaxed into synthesizing the millions of mutational variants of Nef. The researchers then targeted this library, which they call an allelome, with a second library of small-molecule compounds in order to identify the specific compounds that could target the entire population of Nef mutational variants. The results suggest chemically simpler, more flexible compounds could better accommodate viral mutations.

The research is part of a UCI program aimed at expanding the anti-HIV drug arsenal. The program includes National Academy of Sciences member Larry Overman in the Department of Chemistry, who together with co-workers synthesized the small-molecules used in the study. New anti-HIV compounds are being tested by Dr. W. Ed Robinson, Jr. in the Department of Pathology.

Weiss and Olszewski have made their method freely available to the scientific research community. Olszewski is a fourth-year graduate student in the Weiss laboratory. The study was largely supported by a Young Investigator Award to Weiss from the Beckman Foundation.

University of California-Irvine