Researcher Discovers Promising Broad-Range Target for HPV

He has received a $1.65 million grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health to find out if this interaction might lead to a drug that protects against all HPV variations.

The protein sequence Melendy identified is not only necessary for HPV synthesis—it is also highly conserved between all of the 180 HPV isotypes catalogued to date.

These variations make broad-range treatment extremely difficult: While the HPV vaccine protects against the most common infections, it only covers four of the isotypes.

“Currently, no antiviral drugs exist that act directly against HPV,” says Melendy, associate professor in the Department of Microbiology and Immunology.

“For individuals with persistent HPV infections—which has recently been found to be a particular problem among African-American women—a treatment that works against an ongoing HPV infection and acts against all HPV isotypes is exactly what is needed.”

Melendy’s work explains why HPV, unlike other DNA viruses, integrates so readily into the genome of human cells.

The target he and his colleagues have identified, E1, is a protein encoded for in the viral genome that interacts with human-DNA synthesis proteins and enzymes, Melendy explains.

“It is found in all HPV isotypes, and it essentially ‘reprograms’ our DNA to start synthesizing HPV genomes once our cells are infected.”

In particular, Melendy has been studying a protein-protein interaction between E1 and the human enzyme Topol (Topoisomerase I).

In 2010, he identified individual amino acids within the HPV E1 protein that he suspected were critical for interactions with Topol. His lab created an E1 mutation that altered a single amino acid within this conserved domain.

Melendy’s colleague, Jacques-Archambault, PhD, director of the Institut de Recherches Cliniques de Montreal, tested this mutation in a cell-culture HPV DNA synthesis system he had developed.

“The result provided the proof of principle we were seeking,” says Melendy. “It demonstrated, as I had predicted, that this E1 mutant was dramatically compromised for HPV DNA synthesis.”

It turned out that the interaction domain on E1 is one of the most conserved protein sequences across all HPV isotypes.

“That suggested that if we can find a way to interfere with this interaction, we could affect all HPV isotypes—not just some,” says Melendy.

The new grant funds research to further analyze this interaction in order to find out how best to attack it.

In addition to Melendy, other investigators on the grant include Archambault and Vivian Cody, PhD, principal scientist at Hauptman Woodward Medical Research Institute and UB professor of structural biology, who will attempt to co-crystallize Topol with the domain of E1 that interacts with Topol in order to visualize the interaction at the atomic level.

The data will be used to develop a more refined series of small molecules designed to interfere with the E1-Topol interaction, with the ultimate goal of developing a broad-range drug against the virus.