title: Novel antivirals inhibit early steps in HPV infection.
abstract: The future incidence of cervical cancer is forecast to decline because of the remarkably effective prophylactic vaccines against human papillomaviruses. However, lack of access to these expensive vaccines in the developing countries where cervical cancer is most frequent, and the restricted genotypes these vaccines protect against, will limit their impact. Clearly, there is still a need for identifying other modalities for preventing HPV infections. Ready access to effective, inexpensive antivirals represents one potentially valuable approach to the prevention of genital HPV infections. We developed a well-validated high throughput screening (HTS) assay for identifying compounds that inhibit HPV infection and applied this assay to identify lead compounds that act by inhibiting an early step in infection. We screened over 40,000 small molecules that were available at the University of Wisconsin Small Molecule Screening Facility (UW-SMSF). The top 22 compounds were chosen for further analyses based upon the pharmacological property, scaffold diversity, strength of the inhibitory activity and lack of nonspecific cytotoxicity. Of these compounds, #13 and #14 had the most acceptable properties of low to submicromolar IC(50)'s and low cytotoxicity. Optimal antiviral activities were elicited by exposure of cells to the #13 and #14 during the initial 12 h following infection. Twenty-nine #13-like and 15 #14-like analogs were identified in silico and tested for their antiviral activities corresponded to the altered structures comparing to #13 and #14, informing on the pharmacophore structure of each compound. Studies indicate that both compounds inhibit infection post-entry.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States.
authors.forename: Hao-Shun
authors.initials: HS
authors.lastname: Huang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI, United States; Department of Microbiology, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Dohun
authors.initials: D
authors.lastname: Pyeon
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI, United States.
authors.forename: Shane M
authors.initials: SM
authors.lastname: Pearce
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI, United States.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Lank
authors.affiliation: Department of Microbiology, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Griffin
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI, United States; Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI, United States. Electronic address: ahlquist@wisc.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Ahlquist
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States. Electronic address: plambert@wisc.edu.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
mesh_terms: D052685:Alphapapillomavirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D030361:Papillomavirus Infections / Q000188:drug therapy / Q000821:virology*; D054852:Small Molecule Libraries
chemical_list: D000998:Antiviral Agents; D054852:Small Molecule Libraries