title: Sulfated K5 Escherichia coli polysaccharide derivatives as wide-range inhibitors of genital types of human papillomavirus.
abstract: Genital human papillomaviruses (HPV) represent the most common sexually transmitted agents and are classified into low or high risk by their propensity to cause genital warts or cervical cancer, respectively. Topical microbicides against HPV may be a useful adjunct to the newly licensed HPV vaccine. A main objective in the development of novel microbicides is to block HPV entry into epithelial cells through cell surface heparan sulfate proteoglycans. In this study, selective chemical modification of the Escherichia coli K5 capsular polysaccharide was integrated with innovative biochemical and biological assays to prepare a collection of sulfated K5 derivatives with a backbone structure resembling the heparin/heparan biosynthetic precursor and to test them for their anti-HPV activity. Surface plasmon resonance assays revealed that O-sulfated K5 with a high degree of sulfation [K5-OS(H)] and N,O-sulfated K5 with a high [K5-N,OS(H)] or low [K5-N,OS(L)] sulfation degree, but not unmodified K5, N-sulfated K5, and O-sulfated K5 with low levels of sulfation, prevented the interaction between HPV-16 pseudovirions and immobilized heparin. In cell-based assays, K5-OS(H), K5-N,OS(H), and K5-N,OS(L) inhibited HPV-16, HPV-18, and HPV-6 pseudovirion infection. Their 50% inhibitory concentration was between 0.1 and 0.9 mug/ml, without evidence of cytotoxicity. These findings provide insights into the design of novel, safe, and broad-spectrum microbicides against genital HPV infections.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy. david.lembo@unito.it
authors.forename: David
authors.initials: D
authors.lastname: Lembo
authors.forename: Manuela
authors.initials: M
authors.lastname: Donalisio
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.forename: Maura
authors.initials: M
authors.lastname: Cornaglia
authors.forename: Paola
authors.initials: P
authors.lastname: Cappello
authors.forename: Mirella
authors.initials: M
authors.lastname: Giovarelli
authors.forename: Pasqua
authors.initials: P
authors.lastname: Oreste
authors.forename: Santo
authors.initials: S
authors.lastname: Landolfo
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D016667:Bacterial Capsules / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004926:Escherichia coli / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000187:drug effects* / Q000472:pathogenicity; D052161:Human papillomavirus 18 / Q000187:drug effects* / Q000472:pathogenicity; D052163:Human papillomavirus 6 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D013431:Sulfates / Q000737:chemistry*; D020349:Surface Plasmon Resonance; D014771:Virion / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D000998:Antiviral Agents; D013431:Sulfates; C050673:capsular polysaccharide K5; D006493:Heparin