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Mechanisms of Action of Drugs with Dual Or Multiple Antiviral Activities

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Mechanisms of Action of Drugs with Dual Or Multiple Antiviral Activities NOTE TO USERS This reproduction is the best copy available. MECHANISMS OF ACTION OF DRUGS WITH DUAL OR MULTIPLE ANTIVIRAL ACTIVITIES Egor Petrovitch Tchesnokov Department of Microbiology & Immunology McGill University, Montreal June, 2009 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Egor Petrovitch Tchesnokov i Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-61818-9 Our file Notre référence ISBN: 978-0-494-61818-9 NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l’Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L’auteur conserve la propriété du droit d’auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author’s permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n’y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. ABSTRACT Viral enzymes that catalyze replication of the viral genome remain the main subject of currently available antiviral therapies. This work focuses on three anti- viral agents that target viral DNA polymerases: foscarnet, acyclovir and entecavir. Though the broad spectrum of antiviral activities of foscarnet has been recognized for decades, only recently has it been shown that the anti-herpesvirus drug acyclovir and the anti-hepatitis B virus drug entecavir are also active against the human immunodeficiency virus (HIV) 1. The clinical benefits of the multiple antiviral activities of foscarnet have been demonstrated in treating HIV/herpesvirus co-infections. Foscarnet is currently approved for treating human cytomegalovirus infections. But the precise molecular mechanism of foscarnet action and resistance remains poorly understood. The study of foscarnet’s mode of action against the HCMV DNA polymerase (UL54) is complicated in part by the difficulty in expressing and purifying the viral enzyme. To address the first issue, I conducted biochemical studies of foscarnet/UL54 interactions using an unpurified viral enzyme. I then proposed a model based on these studies for the presumptive foscarnet binding site within UL54. To address the second issue I generated the RB69 bacteriophage/HCMV polymerase chimera, which is easily purifiable and displays the UL54 phenotype with respect to foscarnet and acyclovir. The recent discovery of the anti-HIV activity of acyclovir has been followed by a report showing the selection of the V75I mutation within HIV-1 reverse transcriptase (RT) under the selective pressure of acyclovir. My own biochemical studies have revealed that the major effect of V75I substitution involves reducing the catalytic rate of acyclovir incorporation. The recent report of entecavir anti-HIV-1 activity has demonstrated the selection of M184V- containing HIV-1. Subsequent biochemical studies have revealed that M184V- containing RT discriminates against entecavir at the level of incorporation. My own studies show that the major effect of entecavir incorporation has been the delayed chain termination (DCT) of the DNA synthesis. DCT protects the incorporated drug from excision. The research project described in this thesis ii provides novel tools and reveals new concepts for future drug design and development. iii RÉSUMÉ Les enzymes virales qui sont responsables pour la réplication du génome viral constituent l’objet principal des thérapies antivirales actuelles. Ce travail se concentre sur trois agents anti-viraux qui inhibitent les polymérases d’ ADN virales. Malgré le fait que plusieurs activités antivirales du foscarnet sont connues depuis des décennies, il a éte démontré seulement récemment que l’acyclovir, un agent contre le virus de l`herpes, et entecavir, un agent contre le virus de l`hepatite B, ont une activité anti-VIH-1. Les avantages cliniques des multiples activités antivirales du foscarnet dans le traitement des co-infections VIH/herpes ont été démontrés. Le foscarnet est présentement approuvé pour traiter les infections du cytomégalovirus humain. Le mécanisme précis de l’action antivirale du foscarnet, ainsi que le mécanisme de résistance au foscarnet demeurent mal compris. L’étude du mécanisme d’action de foscarnet contre l’ADN polymérase du VCMH (UL54) est compliquée en partie par deux problématiques : l’expression de l’enzyme virale et la purification de cette protéine. Pour adresser le premier problème, j’ai poursuivis des études biochimiques sur les interactions foscarnet- UL54 en utilisant une enzyme virale non-purifiée. En se basant sur ces études, j’ai ensuite proposé un model du site de liaison du foscarnet. Pour addresser le deuxième problème, j’ai généré une protéine chimère bactériophage/HCMV polymérase. Cette protéine est facilement purifiable et possède le profile de la UL54 polymérase envers foscarnet et acyclovir. La découverte récente de l’activité anti-VIH de l’acyclovir a été suivie d`une étude démontrant la sélection de la mutation V75I dans la transcriptase inverse (TI) du VIH-1 sous la pression sélective de l’acyclovir. Mes propres études biochimiques ont révélées que l’effet majeur de la substitution V75I implique la réduction du rythme catalytique de l’incorporation de l’acyclovir. L`étude récente portant sur l’activité anti-VIH-1 d’entecavir a démontré la sélection de TI contenant la mutation M184V. Des études biochimiques subséquentes ont révélées que la TI contenant la M184V démontre une préférence sélective envers l’entecavir au niveau de l’incorporation. Mes propres études démontrent que l’effet majeur se situe au niveau de iv l’abrogation de la synthèse d’ADN ultérieure (ASAU). L’ASAU protège l’entecavir incorporé de l’excision. Le projet de recherche décrit dans cette thèse apporte de nouveaux outils et révèle de nouvelles approches pour la conception et le développement de médicaments. v PREFACE This thesis was written in accordance with McGill University’s “Guideline for Thesis Preparation”. The format of this thesis conforms to the “Manuscript-based thesis” option which states: “Candidates have the option of including, as part of the thesis, the text of one or more papers submitted, or to be submitted, for publication, or the clearly- duplicated text (not the reprints) of one or more published papers. These texts must conform to the "Guidelines for Thesis Preparation" with respect to font size, line spacing and margin sizes and must be bound together as an integral part of the thesis.” Manuscripts included in this thesis: Tchesnokov EP, Gilbert C, Boivin G, Götte M. Role of helix P of the human cytomegalovirus DNA polymerase in resistance and hypersusceptibility to the antiviral drug foscarnet. J Virol. 2006 Feb;80(3):1440-50. Tchesnokov E.P., Obikhod A., Schinazi I. R. F. and Götte M. Engineering of a chimeric RB69 DNA polymerase sensitive to drugs targeting the cytomegalovirus enzyme. Journal of Biological Chemistry. Submitted Tchesnokov E.P., Obikhod A., Massud I., Lisco A., Vanpouille C., Brichacek B., Balzarini J., McGuigan C., Derudas M., Margolis L., Schinazi R. F. and Götte M. Mechanisms associated with HIV-1 resistance to acyclovir by the V75I mutation in reverse transcriptase. Journal of Biological Chemistry. Submitted Tchesnokov EP, Obikhod A, Schinazi RF, and Götte M. Delayed chain-termination protects the anti-HBV drug entecavir from excision by HIV-1 reverse transcriptase. J Biol Chem. 2008 Dec 5;283(49):34218-28 vi The contribution of co-authors to published or submitted articles appears in the section “CONTRIBUTIONS OF AUTHORS”. The journal of submission and information from published articles can be found on the title page of the concerned chapters. Other manuscripts not included in this thesis, but to which a significant contribution was made by the candidate, are listed as follows: Marchand B, Tchesnokov EP, Götte M. The pyrophosphate analogue foscarnet traps the pre-translocational state of HIV-1 reverse transcriptase in a Brownian ratchet model of polymerase translocation. J Biol Chem. 2007 Feb 2;282(5):3337-46. Lisco A, Vanpouille C, Tchesnokov EP, Grivel JC, Biancotto A, Brichacek B, Elliott J, Fromentin E, Shattock R, Anton P, Gorelick R, Balzarini J,
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