title: Small molecule inhibitors of the annexin A2 heterotetramer prevent human papillomavirus type 16 infection.
abstract: OBJECTIVE
  High-risk human papillomavirus (HPV) infection leads to the development of several human cancers that cause significant morbidity and mortality worldwide. HPV type 16 (HPV16) is the most common of the cancer-causing genotypes and gains entry to the basal cells of the epithelium through a non-canonical endocytic pathway that involves the annexin A2/S100A10 heterotetramer (A2t). A2t is composed of two annexin A2 monomers bound to an S100A10 dimer and this interaction is a potential target to block HPV16 infection. Here, recently identified small molecule inhibitors of A2t (A2ti) were investigated for their ability to prevent HPV16 infection in vitro.
  
  
  METHODS
  A2ti were added to HeLa cells in increasing concentrations prior to the addition of HPV16. Cytotoxicity was evaluated via trypan blue exclusion. HPV16 pseudovirion infection and fluorescently labelled HPV16 capsid internalization was measured with flow cytometry.
  
  
  RESULTS
  A2ti blocked HPV16 infection by 100% without substantial cellular toxicity or reduction in cell growth. Furthermore, A2ti blocked HPV16 entry into epithelial cells by 65%, indicating that the observed inhibition of HPV16 infection is in part due to a block in entry and that non-infectious entry may occur in the absence of A2t binding.
  
  
  CONCLUSIONS
  These results demonstrate that targeting A2t may be an effective strategy to prevent HPV16 infection.
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, 2011 Zonal Avenue HMR 401, Los Angeles, CA, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Woodham
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, 2011 Zonal Avenue HMR 401, Los Angeles, CA, USA.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Taylor
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, 2011 Zonal Avenue HMR 401, Los Angeles, CA, USA.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Jimenez
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Skeate
authors.affiliation: Laboratories of Chemical Physics and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, USA.
authors.forename: Heike E
authors.initials: HE
authors.lastname: Brand
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, USA Department of Obstetrics & Gynecology, University of Southern California, 2020 Zonal Avenue Room 220, Los Angeles, CA, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Da Silva
authors.affiliation: Department of Molecular Microbiology & Immunology, University of Southern California, 2011 Zonal Avenue HMR 401, Los Angeles, CA, USA Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, USA Department of Obstetrics & Gynecology, University of Southern California, 2020 Zonal Avenue Room 220, Los Angeles, CA, USA mkast@usc.edu.
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: D017306:Annexin A2 / Q000037:antagonists & inhibitors*; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects*; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D000998:Antiviral Agents
keywords: A2t; HPV16; annexin A2/S100A10 heterotetramer