Antiviral Strategies

386 Pages·2009·7.91 MB·English

by  B. Müller

189
Handbook of Experimental Pharmacology
Hans-Georg Kräusslich
Ralf Bartenschlager
Editors
Antiviral
1
Strategies
AB 3
Handbook of Experimental Pharmacology
Volume 189
Editor-in-Chief
F.Hofmann,München
EditorialBoard
J.Beavo,Seattle,WA
A.Busch,Berlin
D.Ganten,Berlin
J.-A.Karlsson,Singapore
M.Michel,Amsterdam
C.P.Page,London
W.Rosenthal,Berlin
Hans-Georg Kräusslich Ralf Bartenschlager
•
Editors
Antiviral Strategies
Contributors
J.Anderson,R.Bartenschlager,L.C.Bassit,C.Baum,B.Berkhout,C.A.B.Boucher,
S. Chevaliez, S.J. Coats, E. De Clercq, S. Fleßa, J. Haasnoot, G. Hewlett, S.J.
Hurwitz, H.-G.Kräusslich, S.-K. Lee, J. Lennerstrand, P. Marschall, T. Melby,
B.Müller,J.H.Nettles,J.Neyts,M.Nijhuis,J.-M.Pawlotsky,U.Protzer,C.Schiffer,
R.F. Schinazi, P.M. Schmidt, V. Soriano, R. Swanstrom, R. Thomson, N.M. van
Maarseveen, M. von Itzstein, D. von Laer, H. Rübsamen-Waigmann, M. Westby,
S.Zeuzem,H.Zimmermann
ABC
Editors
Hans-GeorgKräusslich RalfBartenschlager
UniversitätsklinikumHeidelberg UniversitätsklinikumHeidelberg
HygieneInstitute HygieneInstitute
DepartmentofVirology DepartmentofMolecularVirology
ImNeuenheimerFeld324 ImNeuenheimerFeld345
69120Heidelberg 69120Heidelberg
Germany Germany
hans-georg_kraeusslich@ [email protected]
med.uni-heidelberg.de
ISBN978-3-540-79085-3 e-ISBN978-3-540-79086-0
HandbookofExperimentalPharmacologyISSN0171-2004
LibraryofCongressControlNumber:2008933564
(cid:176)c Springer-VerlagBerlinHeidelberg2009
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Preface
On the evolutionary scale, viruses are as old as their hosts, and reports or repre-
sentations of viral diseases date back to ancient history. The awareness of viral
pathogens increased in the last 500 years with deadly epidemics of smallpox and
alargedeathtolltakenbymeaslesandinfluenza.Aprimeexampleforadevastat-
ingviralpandemicleavinglittleoptionsforinterventionistheso-calledSpanishflu
in1918/1919,whichdemandedmorevictimsthantheentireworldwarI.Because
of the genetic flexibility of viruses, new strains or species constantly emerge, the
mostprominentexamplebeinghumanimmunodeficiencyvirus(HIV),thecausative
agentofAIDS,whichwasfirstidentifiedintheearly80softhetwentiethcentury.
From the early 1900s on, hygiene measures greatly improved the containment
ofmanyinfectiousdiseases.Furthermore,thediscoveryofantibioticssignificantly
increased the range of therapeutic options against bacterial diseases. These drugs
target bacterial functions such as cell wall integrity, prokaryotic DNA replication,
or protein expression. As obligate intracellular parasites, viruses heavily rely on
host cell functions to achieve efficient replication and thus are not targeted by
these drugs. A crucial discovery, by Enders, Weller, and Robbins in 1949, laying
the ground for the development of antiviral drugs was the ability to cultivate cells
in vitro and infect them with a virus (in this case poliovirus). The first antivirals
were fortuitous discoveries of compounds originally developed for other purposes
butinhibitingthereplicationofoneorseveralvirusesintissueculture.Accordingly,
theirmechanismsofactionwerediscoveredsignificantlyonlylater.
The advent of molecular biology greatly facilitated antiviral drug discovery in
thepast30years,withanunprecedentedeffortbybothacademicresearchandphar-
maceutical industry, leading to approximately 25 HIV-specific drugs from various
classes that are currently in clinical use. Similar drug development strategies are
being pursued for treatment of hepatitis C, with first compounds reaching clini-
cal application. Most antiviral drugs are targeting virus-encoded enzymes essen-
tial for viral replication and sufficiently different from their host counterparts to
achieveacceptabletoxicity(e.g.,polymerases,proteases,endonucleases,sialidases,
andhelicases).Morerecentdrugdiscoveryapproachesaredirectedagainstnonen-
zymaticviralfunctions(e.g.,fusioninhibitors)andcellularfactorsrequiredforviral
v
vi Preface
replication(e.g.,coreceptorantagonists),andthesearecomplementedbytherapeu-
ticapproaches boosting the immune response against viralinfection. Novel devel-
opmentsincludesmallinterfering(si)RNAapproachesthatmayreachclinicaluse
in topical applications (i.e., respiratory diseases), but may only achieve their full
potentialoncegenetherapybecomesafeasibleoption.
Acrucialissueforantiviraltherapyisthefactthatallantiviralsubstancesrapidly
selectforresistance;thus,monitoringandovercomingresistancehasbecomeamost
importantclinicalparadigmofantiviraltherapy.Thiscallsforcautioususeofantivi-
ral drugs and implementation of combination therapies. In parallel, efforts in drug
discovery have to be continued to develop compounds with novel mode-of-action
andactivityagainstresistantstrains.Thisbookreviewsthecurrentstatusofantivi-
raltherapy,fromtheroadstodevelopmentofnewcompoundstotheirclinicaluse
andcosteffectiveness.Individualchaptersaddressinmoredetailallavailabledrug
classesandoutlinenewapproachescurrentlyunderdevelopment.
Wethankthemanyauthorsfortheircontributionstoproducethisvolume.Asau-
thorsourselves,werecognizethedifficultiesofworkingonaprojectofthisnature.
Thefactthatallauthorswerewillingtoacceptchangesintheirchapters,especially
thefrequentreductionoflengthofdrafts,facilitatedoureditorialeffortstoagreat
extent. Furthermore, we thank Sandra Bu¨hler, Antje Keppler, and Barbara Mu¨ller
forcriticalreadingofthemanuscriptsandtheirenormoushelptoadaptthedraftsto
the publisher’s guidelines. We also thank Susanne Dathe, desk editor biomedicine
atSpringer,forhersupportandexperteditorialhelp.
In conclusion, we hope that this volume will be valued by researchers in the
field,andbythosewhoareengagedinthefuturedevelopmentsandapplicationsof
antiviralstrategies.
Heidelberg,Germany Hans-GeorgKra¨usslich
RalfBartenschlager
Contents
AntiviralStrategies.............................................. 1
B.Mu¨llerandH.G.Kra¨usslich
ApproachesfortheDevelopmentofAntiviralCompounds:
TheCaseofHepatitisCVirus ..................................... 25
R.F.Schinazi,S.J.Coats,L.C.Bassit,J.Lennerstrand,J.H.Nettles,
andS.J.Hurwitz
AntiviralAgentsActingasDNAorRNAChainTerminators ........... 53
E.DeClercqandJ.Neyts
ViralProteaseInhibitors ......................................... 85
J.Anderson,C.Schiffer,S.-K.Lee,andR.Swanstrom
Anti-InfluenzaDrugs:TheDevelopment
ofSialidaseInhibitors............................................ 111
M.vonItzsteinandR.Thomson
OtherInhibitorsofViralEnzymesandFunctions .................... 155
H.Zimmermann,G.Hewlett,andH.Ru¨bsamen-Waigmann
InhibitorsofViralEntry ......................................... 177
T.MelbyandM.Westby
InterferonsandTheirUseinPersistentViralInfections ............... 203
S.ChevaliezandJ.-M.Pawlotsky
NucleicAcids-BasedTherapeutics intheBattleAgainstPathogenic
Viruses ........................................................ 243
J.HaasnootandB.Berkhout
AntiviralGeneTherapy .......................................... 265
D.vonLaer,C.Baum,andU.Protzer
vii
viii Contents
Antiviral Resistance and Impact on Viral Replication Capacity:
EvolutionofVirusesUnderAntiviralPressureOccursinThreePhases .. 299
M.Nijhuis,N.M.vanMaarseveen,andC.A.B.Boucher
AntiviralCombinationTherapyforTreatmentofChronicHepatitisB,
HepatitisC,andHumanImmunodeficiencyVirusInfection............ 321
W.P.Hofmann,V.Soriano,andS.Zeuzem
Socio-EconomicImpactofAntiviralIntervention..................... 347
S.FleßaandP.Marschall
Index .............................................................375
Contributors
J.Anderson DivisionofInfectiousDiseases,DepartmentofInternalMedicine,
UniversityofMassachusetts,Worcester,MA,USA
R.Bartenschlager DepartmentofMolecularVirology,ImNeuenheimerFeld
345,69120Heidelberg,Germany,ralf [email protected]
L.C.Bassit LaboratoryofBiochemicalPharmacology,CenterforAIDSResearch,
EmoryUniversitySchoolofMedicine/VeteransAffairsMedicalCenter,Atlanta,
GA30033,USA
C. Baum Department of Experimental Hematology, Hannover Med-
ical School, OE 6960, Carl-Neuberg-Str.1, 30625 Hannover, Germany,
[email protected]
B. Berkhout Laboratory of Experimental Virology, Department of Medical
Microbiology, Center for Infection and Immunity Amsterdam (CINIMA),
AcademicMedicalCenteroftheUniversityofAmsterdam,110,Meibergdreef15,
1105AZAmsterdam,TheNetherlands,[email protected]
C.A.B.Boucher DepartmentofClinicalVirology,Eijkman-WinklerInstitute,
UniversityMedicalCenterUtrecht,TheNetherlands,[email protected]
S. Chevaliez French National Reference Center for Viral Hepatitis B, C and
delta,DepartmentofVirology,HoˆpitalHenriMondor,Universite´ Paris12,Cre´teil,
France
S.J.Coats LaboratoryofBiochemicalPharmacology,CenterforAIDSResearch,
EmoryUniversitySchoolofMedicine/VeteransAffairsMedicalCenter,Atlanta,
GA30033,USA
E. De Clercq Rega Institute for Medical Research, K.U.Leuven,
Minderbroedersstraat10,B-3000Leuven,Belgium,
[email protected]
ix
x Contributors
S. Fleßa Lehrstuhl fu¨r Allgemeine Betriebswirtschaftslehre und
Gesundheitsmanagement, Ernst-Moritz-Arndt-Universita¨t Greifswald,
Friedrich-Loeffler-Straße70-17487Greifswald,Germany,
steffen.fl[email protected]
J. Haasnoot Laboratory of Experimental Virology, Department of Medical
Microbiology, Center for Infection and Immunity Amsterdam (CINIMA),
Academic Medical Center of the University of Amsterdam, Meibergdreef 15,
1105AZAmsterdam,TheNetherlands
G. Hewlett HBSC, Krutscheider Weg 96, 42327 Wuppertal, Germany,
[email protected]
S.J. Hurwitz Laboratory of Biochemical Pharmacology, Center for AIDS
Research,EmoryUniversitySchoolofMedicine/VeteransAffairsMedicalCenter,
Atlanta,GA30033,USA
H.-G.Kra¨usslich DepartmentofVirology,ImNeuenheimerFeld324,69120
Heidelberg,Germany,[email protected]
S.-K. Lee UNC Center For AIDS Research, University of North Carolina at
ChapelHill,ChapelHill,NC27599,USA
J.Lennerstrand LaboratoryofBiochemicalPharmacology, CenterforAIDS
Research,EmoryUniversitySchoolofMedicine/VeteransAffairsMedicalCenter,
Atlanta,GA30033,USA
P. Marschall Lehrstuhl fu¨r Allgemeine Betriebswirtschaftslehre und
Gesundheitsmanagement, Ernst-Moritz-Arndt-Universita¨t Greifswald,
Friedrich-Loeffler-Straße70-17487Greifswald,Germany
T.Melby ClinicalVirologyAssociates,101E.EllerbeeSt.,Durham,NC27704,
USA,[email protected]
B.Mu¨ller DepartmentofVirology,UniversityofHeidelberg,ImNeuenheimer
Feld324,69120Heidelberg,Germany,
Barbara [email protected]
J.H. Nettles Laboratory of Biochemical Pharmacology, Center for AIDS
Research,EmoryUniversitySchoolofMedicine/VeteransAffairsMedicalCenter,
Atlanta,GA30033,USA
J.Neyts RegaInstituteforMedicalResearch,K.U.Leuven,Laboratorium
Virologie en Experimentele Chemotherapie, Minderbroedersstraat 10,
3000Leuven,Belgium,[email protected]
M. Nijhuis Department of Medical Microbiology, University Medical Center
Utrecht,Utrecht,TheNetherlands