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J. Biol. Chem., Vol. 278, Issue 29, 26765-26772, July 18, 2003

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Inhibition of Human Papillomavirus DNA Replication by Small Molecule Antagonists of the E1-E2 Protein Interaction^*

Peter W. White , Steve Titolo , Karine Brault , Louise Thauvette , Alex Pelletier , Ewald Welchner , Lise Bourgon , Louise Doyon , William W. Ogilvie , Christiane Yoakim , Michael G. Cordingley  and Jacques Archambault  ¶

From the Department of Biological Sciences and the Department of Chemistry, Boehringer Ingelheim Ltd., Laval H7S 2G5, Canada

Human papillomavirus (HPV) DNA replication is initiated by recruitment of the E1 helicase by the E2 protein to the viral origin. Screening of our corporate compound collection with an assay measuring the cooperative binding of E1 and E2 to the origin identified a class of small molecule inhibitors of the protein interaction between E1 and E2. Isothermal titration calorimetry and changes in protein fluorescence showed that the inhibitors bind to the transactivation domain of E2, the region that interacts with E1. These compounds inhibit E2 of the low risk HPV types 6 and 11 but not those of high risk HPV types or of cottontail rabbit papillomavirus. Functional evidence that the transactivation domain is the target of inhibition was obtained by swapping this domain between a sensitive (HPV11) and a resistant (cottontail rabbit papillomavirus) E2 type and by identifying an amino acid substitution, E100A, that increases inhibition by 10-fold. This class of inhibitors was found to antagonize specifically the E1-E2 interaction in vivo and to inhibit HPV DNA replication in transiently transfected cells. These results highlight the potential of the E1-E2 interaction as a small molecule antiviral target.

Received for publication, April 7, 2003

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biological Sciences, Boehringer Ingelheim Ltd., 2100 Cunard St., Laval H7S 2G5, Canada. Tel.: 450-682-4640; Fax: 450-682-4642; E-mail: jarchambault{at}lav.boehringer-ingelheim.com.

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