Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats

423 Pages·2005·7.76 MB·English

by  Paul F. Torrence

ANTIVIRAL DRUG DISCOVERY
FOR EMERGING DISEASES
AND BIOTERRORISM THREATS
ANTIVIRAL DRUG
DISCOVERY FOR
EMERGING DISEASES
AND BIOTERRORISM
THREATS
Edited by
Paul F. Torrence
Northern Arizona University
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LibraryofCongressCataloging-in-PublicationData:
Antiviraldrugdiscoveryforemergingdiseasesandbioterrorismthreats/editedbyPaulF.Torrence.
p. ; cm.
Includesbibliographicalreferencesandindex.
ISBN-13978-0-471-66827-5(cloth:alk.paper)
ISBN-100-471-66827-3(cloth:alk.paper)
1.AntiviralAgents. 2.Drugdevelopment 3.Bioterrorism.
[DNLM: 1.AntiviralAgents–therapeuticuse. 2.Bioterrorism–prevention&control.
3.CommunicableDiseases,Emerging–drugtherapy. 4.CommunicableDiseases,Emerging–
prevention&control. 5.DrugDesign.QV268.5A62952005]I.Torrence,PaulF.II.Title.
RM411.A57472005
616.901061–dc22 2004019934
PrintedintheUnitedStatesofAmerica
10987654321
CONTENTS
Preface vii
Contributors ix
1. Introduction: Pestilence, Plague, Bioterrorism 3
PaulF.Torrence
2. Viral Bioterrorism and Antiviral Countermeasures 17
MikeBray
3. Overview of Antiviral Drug Discovery and Development 31
ChristopherK.Tseng
4. Antiviral Drug Targets and Strategies for Emerging
Viral Diseases and Bioterrorism Threats 83
ErikDeClercq
5. Perspectives for the Therapy Against Arenavirus Infections 115
ElsaB.DamonteandCybeleC. Garc´ıa
6. S-Adenosylhomocysteine Hydrolase Inhibitors as a Source
of Anti-Filovirus Agents 139
StewartW.SchnellerandMinminYang
7. Antiviral Strategies for Ebola Virus 153
JillianM.Licata andRonaldN.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
JasonD.GraciandCraigE.Cameron
v
vi CONTENTS
10. Structural Biology of Flaviviral Replication and Opportunities
for Drug Design 223
KrishnaMurthy
11. Confronting New and Old Antiviral Threats: Broad Spectrum
Potential of Prenylation Inhibitors 249
MenasheElazarandJeffreyS.Glenn
12. West Nile Virus: New Targets for Potential Antivirals 263
MatthiasKalitzky,HolgerRohde,andPeter Borowski
13. The Emergence of Pandemic Influenza A:
Bioterrorist Versus Mother Nature 281
JohnS.Oxford,Alison Boyers,AlexMann,andR.Lambkin
14. Discovery and Development of New Antivirals for Smallpox 331
EarlR.Kern
15. Viral Countermeasures to the Host Interferon Response:
Role of the Vaccinia Virus E3L and K3L Genes 353
JeffreyO.Langland,VanessaLancaster,and BertramL.Jacobs
16. Broad-Spectrum Antiviral Prophylaxis: Inhibition of Viral
Infection by Polymer Grafting with Methoxypoly(ethylene glycol) 379
LoriL.McCoyandMarkD.Scott
17. Viral Evasion of the Interferon System: Novel Targets
for Drug Discovery 397
PaulF.TorrenceandLindaPowell
Index 417
PREFACE
When I was just beginning my career at the National Institutes of Health as an
organicchemistwhowished tocontributetomedicine in someway, Iwas advised
to stay away from research on the discovery of antiviral agents sinceviruses 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
meanstoeliminatepolio.Theseweremassiveaccomplishmentsandoptimismwas
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,theaspirationsandwell-beingofmillionsuponmillionsinthedeveloping
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
gamblersshirtsleeve,theinfluenzavirus,wildorbioengineered,remainstheaceof
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
humanalterationsbeganinearnestwiththeintroductionofagriculture,whichbred
a series of formidable viruses, including variola (smallpox) and influenza. Yet the
changeswroughtbyhumansoverthepast10,000yearsmaybedwarfedbywhatwe
have ‘‘accomplished’’ in the past century or so. We have brought about massive
habitat changes,penetrated ecological nicheswithaspeedandthoroughnessnever
known in human history, destroyed ecosystems, contributedsubstantially toglobal
warming,bredresistancetoourbestantibiotics,undergoneuncontainedpopulation
expansion,andintroducedsomuchmobilitythatatanytimeagreatfractionofour
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,
withastrongifnotinvinceablehand,considerthatmanyofthevirusesthatthreaten
Homo sapiens are RNA viruses that exist as quasi-species or ‘‘swarms,’’ always
vii
viii PREFACE
readytoexploitanewniche,alwayspreparedtomeetthechallengeofdrugtherapy
with resistance. And then finally the coup de grace. As unfathomable as it may
seem,therearetheextremistsandzealotswhothreatentouseanysuchagentsthey
can obtain or engineer to carry out their agendas. As enemies of all decent people
onearth,theirhatredmaybedirectedatthemorehighlydevelopednations,butthe
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.Thathasledmetoknowandrespectanumberoffellowtravelersandsome
of them are, I am pleased to say, contributors to this volume. This volume is
intendedtoprovidereasonsforoptimisminviewofthedarkandpessimisticpicture
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,
providedvaluableadviceandpatience.RosalynFarkas,alsoatJohnWiley,helped
pull it all together.
PAUL F. TORRENCE
Northern Arizona University
Flagstaff, Arizona
CONTRIBUTORS
Peter Borowski, University Hospital Hamburg-Eppendorf, Institute for Infectious
Diseases, 20246 Hamburg, Germany
AlisonBoyers,RetroscreenVirology,Ltd.,CentreforInfectiousDiseases,Bart’sandThe
LondonQueenMary’sSchoolofMedicineandDentistry,LondonE14NSUK
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
ElsaB.Damonte, LaboratoriodeVirolog´ıa,DepartamentodeQu´ımicaBiolo´gica,
FacultaddeCienciasExactasyNaturales,UniversidaddeBuenosAires,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
CybeleC.Garc´ıa, LaboratoriodeVirolog´ıa,DepartamentodeQu´ımicaBiolo´gica,
FacultaddeCienciasExactasyNaturales,UniversidaddeBuenosAires,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
x CONTRIBUTORS
Earl R. Kern, Department of Pediatrics, Division of Infectious Diseases, The
University of Alabama at Birmingham, Birmingham, AL 35233 USA
R.Lambkin, RetroscreenVirologyLtd.,CentreforInfectiousDiseases,Bart’sand
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
AlexMann,RetroscreenVirology,Ltd.,CentreforInfectiousDiseases,Bart’sand
TheLondonQueenMary’sSchoolofMedicineandDentistry,LondonE14NSUK
KrishnaMurthy, CenterforBiophysicalSciencesandEngineering,Universityof
Alabama at Birmingham, Birmingham, AL 35294 USA
Vasu Nair, Department of Pharmaceutical and Biomedical Sciences and The
CenterforDrugDiscovery,TheUniversityofGeorgia,Athens,GA30606USA
JohnS.Oxford, RetroscreenVirologyLtd.,CentreforInfectiousDiseases,Bart’sand
TheLondonQueenMary’sSchoolofMedicineandDentistry,LondonE14NSUK
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