Abstract

Noncytotoxic Destruction of dsDNA Viral Episomes: Anti-HPV Agents for Prevention of Cervical Cancer, also Active Against Polyomaviruses, which Modulate the DNA Damage Response

James Bashkin, Professor, University of Missouri–St. Louis

We began an anti-human papillomavirus (HPV) program inspired by Dervan1 and Sugiyama's2 work with hairpin pyrrole-imidazole polyamides. Targeting the Long Control Region of the doubled-stranded circular DNA genome of HPV, we originally hoped to block binding of viral proteins necessary for replication. We made large polyamides in an attempt to minimize their accessibility to human chromatin.3 The large size turned out to be important since activity was only observed for polyamides that bound 10 base pairs, or one full turn of B-form DNA. However, it rapidly became clear that our active molecules were better than theoretically possible for replication inhibitors, and must be causing the active degradation of viral DNA.3 We then discovered broad spectrum activity against HPV16, 18 and 31, all being oncogenic strains.3 We have since conducted preclinical safety studies on a lead and backup, made major discoveries about a new mechanism of action for polyamides and antivirals in which the DNA Damage Response is activated,4,5 and found that our compounds to not obey reported polyamide-DNA binding rules.6,7 We have also discovered tetramethyl-substituted and unsubstituted guanidinium N-termini that improve antiviral activity and begun -omics studies to further probe the mechanism of action. Antiviral results were also extended to other small DNA tumour viruses.8 Recent structures and results will be reported.