Inhibition of gamma secretase blocks HPV infection.
Human papillomaviruses (HPV) are common sexually transmitted pathogens that predispose women to cervical and other anogenital cancers. HPV vaccines can prevent infection by some but not other sexually transmitted HPVs but are too costly for use in much of the world at greatest risk to HPV-associated cancers. Microbicides provide an inexpensive alternative to vaccines. In a high throughput screen, drugs that inhibit the cellular protein complex known as gamma secretase were identified as potential HPV microbicides. gamma Secretase inhibitors (GSIs) inhibited the infectivity of HPV pseudoviruses both in human keratinocytes and in mouse cells, with IC(50) values in the picomolar to the nanomolar range. Using a mouse model, we observed that a GSI could inhibit HPV infection to the same degree as its effectiveness in inhibiting gamma secretase activity in vivo. We conclude that gamma secretase activity is required for HPV infection and that GSIs are effective microbicides against anogenital HPVs.
Huang
Hao-Shun
HS
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine, Madison, WI, USA.
Buck
Christopher B
CB
Lambert
Paul F
PF
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005831:Genital Diseases, Female / Q000188:drug therapy* / Q000821:virology; D052162:Human papillomavirus 16 / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D006801:Humans; D015603:Keratinocytes / Q000821:virology; D051379:Mice; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000821:virology; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053829:Amyloid Precursor Protein Secretases