In a recent publication in Science Advances, researchers at UNMC and the Fred & Pamela Buffett Cancer Center lay a solid foundation for the development of improved antiviral therapies for herpes virus infections.
The team, led by Tahir Tahirov, PhD, of UNMC’s Eppley Institute for Research in Cancer and Allied Diseases and the cancer center, and Ci Ji Lim, PhD, of the University of Wisconsin, has determined the structure of the helicase-primase complex, how it functions and the mechanism to inhibit it.
This is important, Dr. Tahirov said, because DNA replication of human herpes simplex virus type 1 (HSV-1) requires a viral helicase-primase complex comprised of helicase, primase and accessory proteins, which start acting early during replication of viral genome. That makes HP an attractive target for antiviral herpes therapy.
Working with two commonly used drugs, pritelivir and amenamevir, the team explored the structures of the drug-free and drug-bound helicase-primase enzyme to map how both drugs block HP activity.
“These structures reveal the overall architecture of the HP complexes when engaged with DNA,” Dr. Tahirov said. “The inhibitor-bound structures identify the binding sites of pritelivir and amenamevir and provide insights into how these compounds stall HP enzymatic activity.”
That information, Dr. Tahirov said, is where the potential lies for improved therapies.
“Our idea was first to understand how helicase-primase functions, what is its structure and how is this structure related to function?” he said.
After mapping the structure, the team found that the inhibitors inserted between two parts of the HP helicase subunit, which move during DNA unwinding, blocking the movement and thereby inhibiting the enzymes ability to support HSV-1 replication.
This provides a precise target for possible future interventions, Dr. Tahirov said, allowing future research that could possibly reduce the amount or frequency of drugs necessary to achieve inhibition by as much as 100%.
“This would be a major advantage,” he said.
He also said mapping the helicase-primase structure for HSV-1 could provide insight into drug development for other members of the herpes virus family.
Due to the tremendous unmet demand for herpes virus treatments, competition to take the lead in drug development is intense. As a result, several universities and private investors are committing funds in advance. Dr. Tahirov said his team hopes to leverage the competitive edge the new research gives them to attract new funding sources.