Human Immunodeficiency Virus Reverse Transcriptase: A Bench-to-Bedside Success PDF
Preview Human Immunodeficiency Virus Reverse Transcriptase: A Bench-to-Bedside Success
Stuart LeGrice · Matthias Gotte Editors Human Immunodefi ciency Virus Reverse Transcriptase A Bench-to-Bedside Success Human Immunodefi ciency Virus Reverse Transcriptase Stuart LeGrice • Matthias Gotte Editors Human Immunodefi ciency Virus Reverse Transcriptase A Bench-to-Bedside Success Editors Stuart LeGrice Matthias Gotte HIV Drug Resistance Program McGill University National Cancer Institute Montreal, QC, Canada Frederick, MD, USA ISBN 978-1-4614-7290-2 ISBN 978-1-4614-7291-9 (eBook) DOI 10.1007/978-1-4614-7291-9 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2013940181 © Springer Science+Business Media New York 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface The Reverse Transcriptase (RT) of Human Immunodefi ciency Virus Type 1 (HIV- 1) arguably ranks among one of the most extensively studied retroviral enzymes. Heterologous expression and purifi cation of HIV-1 RT in the early 1980s, approval of the fi rst nucleoside analogue RT inhibitor (NRTI) in 1987, discovery of resis- tance to RT inhibitors, and approval of the fi rst nonnucleoside analogue RT inhibi- tor (NNRTI) in 1996 and the various crystal structures of RT with or without bound substrate(s) and/or inhibitors represent only a few of the important milestones that describe a bench-to-bedside success in the continuing effort to combat HIV-1 infection and its consequences. Nucleoside and nonnucleoside RT inhibitors remain important components in frequently used drug regimens to treat the infection. RT inhibitors also play important roles in recently validated strategies to prevent transmission of the virus. The relevance of HIV-1 RT as a drug target has simultaneously triggered interest in basic research studies aimed at providing a more detailed under- standing of interactions between proteins, nucleic acids, and small-molecule ligands in general terms. In light of the ever-growing knowledge on the struc- ture and function of HIV-1 RT, this enzyme serves as a valuable “model sys- tem” in efforts to develop novel experimental tools and to explain biochemical processes. This book is designed to provide an overview of important aspects in past and current HIV-1 RT research, with a focus on mechanistic aspects and translation of knowledge into drug discovery and development. The fi rst section includes chapters with emphasis placed on the coordination of the RT-associated DNA polymerase and ribonuclease H (RNase H) activities. The second covers mechanisms of action and future perspectives associated with NRTIs and NNRTIs, while the third section includes chapters focusing on novel strategies to target the RT enzyme. Chapters of the fi nal part are intended to discuss mechanisms involved in HIV variability and the development of drug resistance. We hope that these contributions will stimulate v vi Preface interest and encourage research aimed at the development of novel RT inhibitors. The lack of bona fi de RNase H inhibitors with potent antiviral activity provides an example for challenges and opportunities in the fi eld. Frederick, MD, USA Stuart LeGrice Montreal, QC, Canada Matthias Gotte In Memoriam: Walter A. Scott February 1, 1943–January 28, 2013 As the publication of this book was nearing completion, the HIV research commu- nity was saddened to learn of the sudden passing of one of its contributors, Walter Scott, professor of biochemistry and molecular biology, University of Miami Miller School of Medicine. For those who did not know Walter personally, he will be remembered for his seminal research that unveiled the mechanism through which HIV-1 RT confers resistance to the nucleoside inhibitor AZT. These fi ndings invigo- rated the fi eld and propelled the careers of many of us. As colleagues who interacted with him personally, we are left with memories of Walter as a quiet and unassuming individual who coupled a passion for his science with a sense of wisdom and humor, and someone who dedicated his life to providing guidance to the many students that passed through his laboratory. The impish smile was rarely absent from Walter’s face, regardless of whether he was discussing important research or conjuring up his next joke. Steve Hughes of the National Cancer Institute and a colleague who closely followed Walter’s research described him as “in every sense, one of the best people in the fi eld.” vii viii In Memoriam: Walter A. Scott Born in Los Angeles and raised in Oregon, Walter received his Ph.D. in physiological chemistry in 1970 from the University of Wisconsin, and following post-doctoral research at the University of California at San Francisco and Johns Hopkins University School of Medicine, he joined the faculty of the University of Miami in 1975. After several years studying gene regulation in SV40, he turned his attention to HIV in 1989, combining his own research program with directing the Pediatric Retrovirology Laboratory of the university’s Pediatric AIDS Clinical Trials Unit. During this time, he also coauthored several papers with his wife, Gwen, a faculty member of the Division of Infectious Diseases. The personal nature of Walter’s interaction with colleagues is perhaps best summarized by Peter Meyer, lead author on the 1998 PNAS publication describing the mechanism of AZT resistance, who recalled that he was “like a hand on your shoulder, not someone looking over your shoulder.” At times when we feel the pres- sure of teaching, conducting research and applying for funding, Walter reminded us that there is a lighter, and equally important, side to life, which he most certainly enjoyed to the fullest. His namesake and Scottish novelist once commented that “a sound head, an honest heart, and a humble spirit are the three best guides through time and to eternity.” Walter was endowed with each of these attributes, and will be dearly missed. Contents 1 Development of the First AIDS Drugs: AZT and Other Dideoxynueosides ................................................................................... 1 Robert Yarchoan and Hiroaki Mitsuya Part I Structure and Function of HIV RT 2 Proviral DNA Synthesis in HIV: Background ..................................... 23 Dorota Piekna-Przybylska and Robert A. Bambara 3 The RNase H Domain: Structure, Function and Mechanism ............ 53 Marcin Nowotny and Małgorzata Figiel 4 Conformational Dynamics of Reverse Transcription ......................... 77 Stuart F.J. LeGrice Part II Mechanism of Action of Approved RT Inhibitors 5 Nucleoside RT Inhibitors: Structural and Molecular Biology ........... 99 Gaofei Lu, Antonio J. Acosta-Hoyos, and Walter A. Scott 6 Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) .............. 123 Kalyan Das, Eddy Arnold, and Stephen H. Hughes Part III Alternative Strategies to Interfere with the Function of HIV RT 7 Ribonuclease H Inhibitors: Structural and Molecular Biology ......... 143 Jason W. Rausch 8 Targeting Small Molecules and Peptides to the p66-p51 Reverse Transcriptase Interface ............................................ 173 Daouda Abba Moussa, Audrey Agopian, and Gilles Divita ix
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