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

White, Peter W.; Faucher, Anne-Marie; Massariol, Marie-Josée; Welchner, Erika; Rancourt, Jean; Cartier, Mireille et Archambault, Jacques (2005). « Biphenylsulfonacetic Acid Inhibitors of the Human Papillomavirus Type 6 E1 Helicase Inhibit ATP Hydrolysis by an Allosteric Mechanism Involving Tyrosine 486 ». Antimicrobial Agents and Chemotherapy, 49(12), pp. 4834-4842.

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Résumé

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.

Type: Article de revue scientifique
Mots-clés ou Sujets: allosterism; article; DNA replication; drug potency; enzyme activity; epithelium; Human papillomavirus type 6; IC 50; mutagenesis; nonhuman; pathogenesis; priority journal; structure activity relation; virus infection; virus inhibition; virus replication
Unité d'appartenance: Faculté des sciences > Département de chimie
Déposé par: delegation Jean Rancourt
Date de dépôt: 18 mai 2016 19:48
Dernière modification: 18 mai 2016 19:48
Adresse URL : http://www.archipel.uqam.ca/id/eprint/8474

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