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Virol Res J 2017 Volume 1 Issue 3
International Virology Conference
October 30-31, 2017 | Toronto, Canada
Noncytolytic destruction of dsDNA viral episomes: Anti-HPV agents for prevention of cervical and
other cancers which modulate the DNA damage response and are also active against polyomaviruses
James K Bashkin
Oxford University, UK
O
ur program on anti-human papillomavirus (HPV) compounds
was inspired by Dervan and Sugiyama’s work with hairpin
pyrrole-imidazole polyamides, but nothing we believed initially
turned out to be true even though we discovered very active
compounds. We initially targeted the long control region of
the doubled-stranded, circular, negatively super-coiled DNA
genome of HPV, hoping to block binding of viral proteins
necessary for replication. We made large polyamides in an
attempt to minimize their accessibility to human chromatin,
and this size turned out to be important because activity was
observed only for polyamides that bound at least one full turn
of B-form DNA. However, it was immediately obvious that
our active molecules were more powerful than theoretically
possible for replication inhibitors. In fact, after further
experimentation, we found that antiviral polyamides were
causing active degradation of viral DNA. We were surprised
to discover broad spectrum activity against HPV16, 18 and 31,
all oncogenic strains, given the reported rules for polyamide-
DNA recognition on which our structures were originally based.
More recently, we conducted preclinical safety studies on lead
and backup compounds, discovered a new mechanism of
action for polyamides and antivirals in which the DNA Damage
Response is activated and found that our compounds fail to
follow reported polyamide-DNA binding rules. We discovered
various guanidinium N-termini that improved antiviral activity,
and we embarked on massively parallel sequencing-based
studies to further probe the mechanism of action. Antiviral
results were also extended to other small DNA tumor viruses,
the polyomaviruses SV40, BKV-Dun, and BKV-TU.
Speaker Biography
James K Bashkin completed his DPhil from Oxford University (UK) and Post-doctoral
studies from Harvard University. He is the Professor of Chemistry and Biochemistry
at the University of Missouri- St. Louis and is the Director of Chemistry at NanoVir, a
company he co-founded. He has published more than 70 papers in reputed journals,
15 issued US patents, and served as an associate editor and Editorial Board Member
for the Royal Society of Chemistry and American Chemical Society. He received the
Thomas and Hochwalt Prize (1994), Presidential Green Chemistry Challenge Award
(1998), and Roland Tibbetts Award (2006).
e:
bashkinj@umsl.edu