Antiviral Polyamides Active Against High-Risk Human Papillomavirus; A New Mechanism for Polyamide Action

Wednesday, 26 April 2017 - 4:10pm - 5:30pm
LD 010

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 anti-HPV activity was only observed for polyamides that bound at least ten 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, important oncogenic strains.3 We have since conducted preclinical safety studies on a lead and backup and discovered a new mechanism of action for polyamides and antivirals in which the DNA Damage Response is activated to destroy viral DNA.4,5 We further found that our compounds do not obey reported polyamide-DNA binding rules.6,7 These studies were conducted with biophysical techniques such as quantitative DNase I footprinting and hydroxyl radical-based affinity cleavage coupled to capillary electrophoresis, and fluorescence assays.8  We also discovered tetramethyl-substituted and unsubstituted guanidinium N-termini that improve antiviral activity,9 and we began -omics studies to further probe the mechanism of action. Antiviral results were also extended to other small DNA tumor viruses.10 Recent compounds and results will be reported.
    (1)    Yang, F.; Nickols, N. G.; Li, B. C.; Szablowski, J. O.; Hamilton, S. R.; Meier, J. L.; Wang, C.-M.; Dervan, P. B. J. Med. Chem. 2013, 56, 7449.
    (2)    Saha, A.; Pandian, G. N.; Sato, S.; Taniguchi, J.; Hashiya, K.; Bando, T.; Sugiyama, H. Bioorg. Med. Chem. 2013, 21, 4201.
    (3)    Edwards, T. G.; Koeller, K. J.; Slomczynska, U.; Fok, K.; Helmus, M.; Bashkin, J. K.; Fisher, C. Antiviral Res. 2011, 91, 177.
    (4)    Edwards, T. G.; Helmus, M. J.; Koeller, K.; Bashkin, J. K.; Fisher, C. J. Virol. 2013, 87, 3979.
    (5)    Edwards, T. G.; Vidmar, T. J.; Koeller, K.; Bashkin, J. K.; Fisher, C. PLOS One 2013, 8, e75406.
    (6)    He, G.; Vasilieva, E.; Harris, G. D.; Koeller, K. J.; Bashkin, J. K.; Dupureur, C. M. Biochimie 2014, 102, 83.
    (7)    Vasilieva, E.; Niederschulte, J.; Song, Y.; Harris, G. D.; Koeller, K. J.; Liao, P.; Bashkin, J. K.; Dupureur, C. M. Biochimie 2016, 127, 103.
    (8)   Dupureur, C. M.; Bashkin, J. K.; Aston, K.; Koeller, K. J.; Gaston, K. R.; He, G. Anal Biochem 2012, 423, 178-83.
    (9)   Castaneda, C. H.; Scuderi, M. J.; Edwards, T. G.; G. Davis Harris, J.; He, G.; Dupureur, C. M.; Koeller, K. J.; Fisher, C.; Bashkin, J. K. MedChemComm 2016, 7, 2076-2082.
    (10)    Bashkin, J. K.; Edwards, T. G.; Fisher, C.; Harris, G. D., Jr.; Koeller, K. J.; US Patent Application 14/818881, publication date: November 19, 2015, 34 pp.