Nouri Neamati, assistant professor of pharmaceutical sciences in the USC School of Pharmacy, and his research group have published a study, featured as the cover story in the June 27 issue of the Proceedings of the National Academy of Sciences, that identifies a new drug-binding site in a viral enzyme critical for HIV replication.

“Integrase plays a key role in the viral replication cycle,” Neamati said. “Targeting this enzyme with a viable drug has the potential to reduce the viral load in infected individuals and act synergistically with currently used drug regimens.”

Neamati’s group used an interesting approach to discover the inhibitor-binding site.

Since the enzyme they were studying was not amenable to traditional techniques, including X-ray crystallographic or nuclear magnetic resonance, the group devised an alternative study route.

First, the researchers irreversibly attached the inhibitor to the viral enzyme integrase, using ultraviolet light. Then, the binding site was identified using mass spectrometry and validated through mutagenesis and enzymatic assays.

According to the published article, the group also conducted molecular modeling studies to gain insight into how the small molecule actually inhibits the viral enzyme.

“Nouri’s ability to utilize molecular modeling tools at the computer – in combination with his expertise in biochemistry and cell biology at the bench – have enabled him to establish a unique niche in the design of new drugs for the treatment of AIDS,” said Sarah Hamm-Alvarez, Gavin S. Herbert Professor of Pharmaceutical Sciences and interim chair of pharmaceutical sciences in the USC School of Pharmacy.

Currently, there are no FDA-approved drugs targeting integrase for HIV treatment. While three other molecules have entered clinical trials over the past five years, these molecules are all suspected to bind to the active site of the enzyme.

Remarkably, the inhibitor used in Neamati’s study was found to bind to a completely different area of the integrase enzyme, not the active site. This is the first study to identify an alternative drug-binding site in the protein, providing a new site for HIV drug-design strategies. Such discoveries could have a major impact in the design of future antiviral drugs.

Integrase is a multi-subunit enzyme, meaning that it requires multiple copies of itself to work correctly. Once the inhibitor binds to integrase, it appears to disrupt the subunit formation, therefore stopping integrase from working. This is the first study to describe a small molecule inhibitor that potentially disrupts integrase formation.

“We predict that small molecule inhibitors designed to bind to this new site that we identified will be synergistic with existing drugs, “ said Laith Al-Mawsawi, a Ph.D. candidate in pharmaceutical sciences who is the first author on the paper. “Our results should have a major impact in the field of HIV drug design targeting integrase.”

Neamati is a leading researcher in the HIV-1 integrase drug design and development field. This article, his fourth on integrase to be published in the Proceedings of the National Academy of Sciences, was accepted as a direct submission to the journal.

The research was predominantly conducted in the USC School of Pharmacy in collaboration with scientists from the University of North Carolina in Chapel Hill, the Katholieke University in Flanders, Belgium and the Medicinal Chemistry Laboratory of the NIH in Frederick, Md.

The work was supported by the USC Zumberge Award, UniversityWide AIDS Research Program, GlaxoSmithKline Drug Discovery and Development Award, and Gustavus and the Louise Pfeiffer Research Foundation to Nouri Neamati.