AntiViral Drug Discovery for Emerging Diseases and BioTerrorism Threats - P. Torrence (Wiley, 2005) WW

436 Pages·2005·5.6 MB·English

ANTIVIRAL DRUG
DISCOVERY FOR
EMERGING DISEASES
AND BIOTERRORISM
THREATS

Edited by

Paul F. Torrence
Northern Arizona University

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright # 2005 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Antiviral drug discovery for emerging diseases and bioterrorism threats/edited by Paul F. Torrence.
p. ;
cm.
Includes bibliographical references and index.
ISBN-13 978-0-471-66827-5 (cloth : alk. paper)
ISBN-10 0-471-66827-3 (cloth : alk. paper)
1. Antiviral Agents.
2. Drug development
3. Bioterrorism.
[DNLM:
1. Antiviral Agents – therapeutic use.
2. Bioterrorism – prevention & control.
3. Communicable Diseases, Emerging – drug therapy.
4. Communicable Diseases, Emerging –
prevention & control.
5. Drug Design. QV 268.5 A6295 2005] I. Torrence, Paul F. II. Title.

RM411.A5747 2005
616.901061–dc22
2004019934

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

CONTENTS

Preface
vii

Contributors
ix

1. Introduction: Pestilence, Plague, Bioterrorism
3
Paul F. Torrence

2. Viral Bioterrorism and Antiviral Countermeasures
17
Mike Bray

3. Overview of Antiviral Drug Discovery and Development
31
Christopher K. Tseng

4. Antiviral Drug Targets and Strategies for Emerging
Viral Diseases and Bioterrorism Threats
83
Erik De Clercq

5. Perspectives for the Therapy Against Arenavirus Infections
115
Elsa B. Damonte and Cybele C. Garcı´a

6. S-Adenosylhomocysteine Hydrolase Inhibitors as a Source
of Anti-Filovirus Agents
139
Stewart W. Schneller and Minmin Yang

7. Antiviral Strategies for Ebola Virus
153
Jillian M. Licata and Ronald N. Harty

8. IMPDH Inhibitors: Discovery of Antiviral Agents
Against Emerging Diseases
179
Vasu Nair

9. Lethal Mutagenesis: Exploiting Error-Prone Replication
of Riboviruses for Antiviral Therapy
203
Jason D. Graci and Craig E. Cameron

v

10. Structural Biology of Flaviviral Replication and Opportunities
for Drug Design
223
Krishna Murthy

11. Confronting New and Old Antiviral Threats: Broad Spectrum
Potential of Prenylation Inhibitors
249
Menashe Elazar and Jeffrey S. Glenn

12. West Nile Virus: New Targets for Potential Antivirals
263
Matthias Kalitzky, Holger Rohde, and Peter Borowski

13. The Emergence of Pandemic Influenza A:
Bioterrorist Versus Mother Nature
281
John S. Oxford, Alison Boyers, Alex Mann, and R. Lambkin

14. Discovery and Development of New Antivirals for Smallpox
331
Earl R. Kern

15. Viral Countermeasures to the Host Interferon Response:
Role of the Vaccinia Virus E3L and K3L Genes
353
Jeffrey O. Langland, Vanessa Lancaster, and Bertram L. Jacobs

16. Broad-Spectrum Antiviral Prophylaxis: Inhibition of Viral
Infection by Polymer Grafting with Methoxypoly(ethylene glycol)
379
Lori L. McCoy and Mark D. Scott

17. Viral Evasion of the Interferon System: Novel Targets
for Drug Discovery
397
Paul F. Torrence and Linda Powell

Index
417

vi
CONTENTS

PREFACE

When I was just beginning my career at the National Institutes of Health as an
organic chemist who wished to contribute to medicine in some way, I was advised
to stay away from research on the discovery of antiviral agents since viruses were
well under control. That was when the World Health Organization nearly had
eliminated variola virus, the causative agent of smallpox and the worst killer in
human history. Years earlier, Salk, Sabin, and Koprowski had given the world the
means to eliminate polio. These were massive accomplishments and optimism was
only natural. Of course, the antiviral naysayers could not read the future. And the
future contained HIV/AIDS...and Ebola hemorrhagic fever...and West Nile virus.
Respiratory syncytial virus, a significant cause of morbidity and mortality among
infants and children, expanded its host range to the elderly and the immunosup-
pressed. Epidemics of herpes and viral hepatitis became commonplace. Cytome-
galovirus also took advantage of the biological niche provided by the unfortunate
immunosuppressed. Yellow fever continued to attack, along with a host of other
diseases, the aspirations and well-being of millions upon millions in the developing
world, while simultaneously undermining economies and providing conditions for
unrest and extremism. Virus names such as Nipah, Hendra, and the SARS virus
became part of the common lexicon. And all the while, waiting like a card up a
gamblers shirt sleeve, the influenza virus, wild or bioengineered, remains the ace of
spades. The human toll of the 1918–1919 ‘‘Spanish’’ flu will never be known
accurately, but best estimates are 20–40 million dead.
We have changed the world dramatically in the past few decades. Indeed the
human alterations began in earnest with the introduction of agriculture, which bred
a series of formidable viruses, including variola (smallpox) and influenza. Yet the
changes wrought by humans over the past 10,000 years may be dwarfed by what we
have ‘‘accomplished’’ in the past century or so. We have brought about massive
habitat changes, penetrated ecological niches with a speed and thoroughness never
known in human history, destroyed ecosystems, contributed substantially to global
warming, bred resistance to our best antibiotics, undergone uncontained population
expansion, and introduced so much mobility that at any time a great fraction of our
number is crossing even the oceans that once provided a barrier to species
migration.
If all this were not enough to provide diseases, including those of viral origin,
with a strong if not invinceable hand, consider that many of the viruses that threaten
Homo sapiens are RNA viruses that exist as quasi-species or ‘‘swarms,’’ always

vii

ready to exploit a new niche, always prepared to meet the challenge of drug therapy
with resistance. And then finally the coup de grace. As unfathomable as it may
seem, there are the extremists and zealots who threaten to use any such agents they
can obtain or engineer to carry out their agendas. As enemies of all decent people
on earth, their hatred may be directed at the more highly developed nations, but the
result of their bioterrorism may set the struggling people of developing countries
back a thousand years. Imagine reintroduction of smallpox to a continent already
fighting the burden of HIV/AIDS, yellow fever, dengue, Ebola, malaria, river
blindness, and on and on.
In spite of the counsel I received to let antivirals alone, I fulfilled my contrary
nature. That has led me to know and respect a number of fellow travelers and some
of them are, I am pleased to say, contributors to this volume. This volume is
intended to provide reasons for optimism in view of the dark and pessimistic picture
I just painted above.
The journal Emerging Infections Diseases kindly cooperated on the use of
certain of their covers throughout the book, and the editior and authors are deeply
grateful for this.
Several individuals have been very helpful in the compilation of this effort.
Bonnie Johnson provided excellent editorial assistance. Polyxeni Potter of Emer-
ging Infectious Diseases provided assistance in garnering permission to reproduce
covers from the journal. Amy Romano, Assistant Editor at John Wiley & Sons,
provided valuable advice and patience. Rosalyn Farkas, also at John Wiley, helped
pull it all together.

PAUL F. TORRENCE
Northern Arizona University
Flagstaff, Arizona

viii
PREFACE

CONTRIBUTORS

Peter Borowski, University Hospital Hamburg-Eppendorf, Institute for Infectious
Diseases, 20246 Hamburg, Germany

AlisonBoyers,RetroscreenVirology,Ltd.,CentreforInfectiousDiseases,Bart’sandThe
London Queen Mary’s School of Medicine and Dentistry, London E1 4NS UK

Mike Bray, Biodefense Clinical Research Branch, OCR/OD/NIAID, National
Institutes of Health, Bethesda, MD 20892 USA

Craig E. Cameron, Department of Biochemistry and Molecular Biology, Penn-
sylvania State University, University Park, PA 16802 USA

Elsa B. Damonte, Laboratorio de Virologı´a, Departamento de Quı´mica Biolo´gica,
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad
Universitaria, 1428 Buenos Aires, Argentina

Erik De Clercq, Rega Institute for Medical Research, Katholieke Universiteit
Leuven, B-3000 Leuven, Belgium

Menashe Elazar, Division of Gastroenterology and Hepatology, Stanford Uni-
versity School of Medicine, Palo Alto, CA 94305 USA

Cybele C. Garcı´a, Laboratorio de Virologı´a, Departamento de Quı´mica Biolo´gica,
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad
Universitaria, 1428 Buenos Aires, Argentina

Jeffrey S. Glenn, Division of Gastroenterology and Hepatology, Stanford Uni-
versity School of Medicine, and Veterans Administration Medical Center, Palo
Alto, CA 94305 USA

Jason D. Graci, Department of Biochemistry and Molecular Biology, Pennsylva-
nia State University, University Park, PA 16802 USA

Ronald N. Harty, Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, PA 19104 USA

Bertram L. Jacobs, School of Life Sciences/Biodesign Institute, Arizona State
University, Tempe, AZ 85287 USA

Matthias Kalitzky, University Hospital Hamburg-Eppendorf, Institute for Infec-
tious Diseases, 20246 Hamburg, Germany

ix

Earl R. Kern, Department of Pediatrics, Division of Infectious Diseases, The
University of Alabama at Birmingham, Birmingham, AL 35233 USA

R. Lambkin, Retroscreen Virology Ltd., Centre for Infectious Diseases, Bart’s and
The London Queen Mary’s School of Medicine and Dentistry, London E1 4NS
UK

Vanessa Lancaster, School of Life Sciences/Biodesign Institute, Arizona State
University, Tempe, AZ 85287 USA

Jeffrey O. Langland, School of Life Sciences/Biodesign Institute, Arizona State
University, Tempe, AZ 85287 USA

Jillian M. Licata, Department of Pathobiology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, PA 19104 USA

Lori L. McCoy, Canadian Blood Services and Department of Pathology and
Laboratory Medicine, University of British Columbia, Vancouver, BC V6T
2B5 Canada

Alex Mann, Retroscreen Virology, Ltd., Centre for Infectious Diseases, Bart’s and
The London Queen Mary’s School of Medicine and Dentistry, London E1 4NS UK

Krishna Murthy, Center for Biophysical Sciences and Engineering, University of
Alabama at Birmingham, Birmingham, AL 35294 USA

Vasu Nair, Department of Pharmaceutical and Biomedical Sciences and The
Center for Drug Discovery, The University of Georgia, Athens, GA 30606 USA

John S. Oxford, Retroscreen Virology Ltd., Centre for Infectious Diseases, Bart’s and
The London Queen Mary’s School of Medicine and Dentistry, London E1 4NS UK

Linda Powell, Department of Chemistry and Biochemistry, Northern Arizona
University, Flagstaff, AZ 86011 USA

Holger Rohde, University Hospital Hamburg-Eppendorf, Institute for Infectious
Diseases, 20246 Hamburg, Germany

Stewart W. Schneller, Department of Chemistry and Biochemistry, Auburn
University, Auburn, AL 36849 USA

Mark D. Scott, Canadian Blood Services and Department of Pathology and
Laboratory Medicine, University of British Columbia, Vancouver, BC V6T
2B5 Canada

Paul F. Torrence, Department of Chemistry and Biochemistry, Northern Arizona
University, Flagstaff, AZ 86011 USA

Christopher K. Tseng, Antiviral Research and Antimicrobial Chemistry, DMID/
NIAID, National Institutes of Health, Bethesda, MD 20892 USA

Minmin Yang, Department of Chemistry and Biochemistry, Auburn University,
Auburn, AL 36849 USA

x
CONTRIBUTORS