Harmless Virus May Hold Key To More Effective HIV Drug Discovery

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

Weiss and Olszewski found that the bacteriophage can modelmillions of different mutational variants of an HIV protein called Nef.Knowing how the entire population of Nef variants responds to new drugsgives researchers greater ability to identify broad-spectrum, anti-HIVcompounds. This approach, Weiss said, can make drug discovery effortsfor 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 ofchemists and biologists," said Weiss, an assistant professor ofchemistry and molecular biology and biochemistry. "By recruiting aharmless virus, we're learning how HIV will respond to new classes ofanti-viral drugs before these compounds are tested in the clinic, whichis currently an expensive and time-consuming process."

The Weiss laboratory specializes in developing massivelibraries of proteins that can potentially target and bind to otherproteins, using a process called phage display. In this study, Weissand Olszewski first created one such library by attaching the Nefprotein onto the bacteriophage, which was then coaxed into synthesizingthe millions of mutational variants of Nef. The researchers thentargeted this library, which they call an allelome, with a secondlibrary of small-molecule compounds in order to identify the specificcompounds that could target the entire population of Nef mutationalvariants. The results suggest chemically simpler, more flexiblecompounds could better accommodate viral mutations.

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

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