A possible target for broad-range HPV therapeutics emerges

May 22, 2012

(Medical Xpress) -- Among viruses, human papilloma virus (HPV) stands out: with more than 180 distinct isotypes or variations catalogued to date, it presents an extremely difficult target for broad-range treatments. And while the HPV vaccine provides protection against the most common HPV infections, it only covers four of the 180-plus isotypes.

But now a University at Buffalo microbiologist has identified a that could present the first viable, broad-range HPV . This in the viral system is not only necessary for HPV synthesis, it is highly conserved between all HPV isotypes.

To find out if this interaction might be the basis of a drug that would work against all HPV isotypes, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health has awarded a $1.65 million grant to Thomas Melendy, PhD, associate professor in the Department of Microbiology and Immunology and the Department of Biochemistry in the UB School of Medicine and Biomedical Sciences.

"Currently, no antiviral drugs exist that act directly against HPV," says Melendy, whose laboratory is a world leader in identifying critical interactions between the HPV proteins and human proteins that the virus uses to duplicate . His work explains why HPV, unlike other DNA viruses, integrates so readily into the genome of human cells.

The target Melendy and his colleagues have identified is E1, a protein found in all HPV isotypes.

"E1 is a protein encoded for in the that interacts with human-DNA synthesis proteins and enzymes," explains Melendy. "It is found in all 180-plus HPV isotypes and it essentially 'reprograms' our synthesis machinery to start synthesizing HPV genomes once our cells are infected."

In particular, Melendy has been studying a protein-protein interaction called E1-Topol in which E1 interacts with the human enzyme Topol (Topoisomerase I).

In 2010, Melendy identified individual amino acids within the HPV E1 protein that he suspected were critical for the interactions with Topol. His lab created a mutation of E1 that altered a single amino acid within this conserved domain. Melendy's colleague, Jacques-Archambault, 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, "demonstrating, as I had predicted, that this E1 mutant was dramatically compromised for HPV DNA synthesis, thus proving that if we could find a way to interfere with this E1-Topol interaction, it should prevent the HPV virus from reproducing."

It turned out that that 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 and not just some," says Melendy.

The new grant funds research designed 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.

All of this information will then 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 anti-HPV drug.

"For individuals with persistent , which has recently been found to be a particular problem among African-American women, for example, a treatment that works against an ongoing HPV infection and that acts against all HPV isotypes is exactly what is needed," says Melendy.

Explore further: 'Get vaccinated,' says HPV expert at UB Medical School

Related Stories

'Get vaccinated,' says HPV expert at UB Medical School

October 11, 2011
(Medical Xpress) -- A University at Buffalo microbiologist whose lab has been studying the human papilloma virus for years, says that parents should have their children vaccinated with Gardasil, the HPV vaccine.

Oral HPV infection, HPV-related cancers more common in men

January 26, 2012
Oral HPV infection is more common among men than women, explaining why men are more prone than women to develop an HPV related head and neck cancer, according to a study presented at the Multidisciplinary Head and Neck Cancer ...

HIV drug could prevent cervical cancer

May 3, 2011
A widely used HIV drug could be used to prevent cervical cancer caused by infection with the human papilloma virus (HPV), say scientists.

Recommended for you

Scientists develop novel 'dot' system to improve cancer detection

August 24, 2017
Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have developed a proof-of-concept nanosystem that dramatically improves the visualization of tumors. Published today in Nature Communications, the platform ...

Study provides insight into link between two rare tumor syndromes

August 22, 2017
UCLA researchers have discovered that timing is everything when it comes to preventing a specific gene mutation in mice from developing rare and fast-growing cancerous tumors, which also affects young children. This mutation ...

Retaining one normal BRCA gene in breast, ovarian cancers influences patient survival

August 22, 2017
Determining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little ...

Study identifies miR122 target sites in liver cancer and links a gene to patient survival

August 22, 2017
A new study of a molecule that regulates liver-cell metabolism and suppresses liver-cancer development shows that the molecule interacts with thousands of genes in liver cells, and that when levels of the molecule go down, ...

Zebrafish larvae could be used as 'avatars' to optimize personalized treatment of cancer

August 21, 2017
Portuguese scientists have for the first time shown that the larvae of a tiny fish could one day become the preferred model for predicting, in advance, the response of human malignant tumors to the various therapeutic drugs ...

Scientists discover vitamin C regulates stem cell function, curbs leukemia development

August 21, 2017
Not much is known about stem cell metabolism, but a new study from the Children's Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.