BUFFALO, N.Y. -- 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
protein interaction that could present the first viable,
broad-range HPV drug target. This protein sequence in the viral DNA
synthesis system is not only necessary for HPV synthesis, it is
highly conserved between all HPV isotypes.
To find out if this protein 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 viral DNA. 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 viral genome 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 human DNA 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,"
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
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 HPV infections, 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.