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Antimicrobial Agents and Chemotherapy, December 2005, p. 4834-4842, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4834-4842.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Biphenylsulfonacetic Acid Inhibitors of the Human Papillomavirus Type 6 E1 Helicase Inhibit ATP Hydrolysis by an Allosteric Mechanism Involving Tyrosine 486

Peter W. White,^1* Anne-Marie Faucher,² Marie-Josée Massariol,¹ Ewald Welchner,¹ Jean Rancourt,² Mireille Cartier,¹ and Jacques Archambault^1,

Department of Biological Sciences,¹ Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., Laval, Quebec, Canada H7S 2G5²

Received 18 July 2005/ Returned for modification 22 September 2005/ Accepted 4 October 2005

Human papillomaviruses (HPVs) are the causative agents of benign and malignant lesions of the epithelium. Despite their high prevalence, there is currently no antiviral drug for the treatment of HPV-induced lesions. The ATPase and helicase activities of the highly conserved E1 protein of HPV are essential for viral DNA replication and pathogenesis and hence are considered valid antiviral targets. We recently described novel biphenylsulfonacetic acid inhibitors of the ATPase activity of E1 from HPV type 6 (HPV6). Based on kinetics and mutagenesis studies, we now report that these compounds act by an allosteric mechanism. They are hyperbolic competitive inhibitors of the ATPase activity of HPV6 E1 and also inhibit its helicase activity. Compounds in this series can also inhibit the ATPase activity of the closely related enzyme from HPV11; however, the most potent inhibitors of HPV6 E1 are significantly less active against the type 11 protein. We identified a single critical residue in HPV6 E1, Tyr-486, substituted by a cysteine in HPV11, which is primarily responsible for this difference in inhibitor potency. Interestingly, HPV18 E1, which also has a tyrosine at this position, could be inhibited by biphenylsulfonacetic acid derivatives, thereby raising the possibility that this class of inhibitors could be optimized as antiviral agents against multiple HPV types. These studies implicate Tyr-486 as a key residue for inhibitor binding and define an allosteric pocket on HPV E1 that can be exploited for future drug discovery efforts.

Present address: Institut de Recherches Cliniques de Montreal, 110 Pine Ave. West, Montreal, Quebec, Canada H2W 1R7.