Antiviral Agents

372 Pages·2013·15.104 MB·1-369\372

by  Erik De Clercq (Eds.)

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PREFACE
Theyear1929,whenFlemingpublishedhisseminalpaperontheantibacterial
actionofapenicillium(Fleming,1929),isgenerallyconsideredastheyearof
birth of the antibiotic era. The birthday of the antivirals (De Clercq, 2009;
Field&DeClercq,2004)was30yearslaterwhenPrusoffdescribedthesyn-
0
thesis of 5-iodo-2-deoxyuridine (IDU) (Prusoff, 1959). After Herrmann
describeditsantiviralactivityinvitro(Herrmann,1961)andKaufmanitseffi-
cacyinthetreatmentofherpessimplexvirus(HSV)keratitis(Kaufman,1962),
IDUbecamethefirstantiviraltobeusedtopicallyforthetreatmentofherpetic
eyeinfections.Twoyearslater,in1964,KaufmanandHeidelbergerdescribed
0
the antiviral action of 5-trifluoro-2-deoxythymidine (TFT) (Kaufman &
Heidelberger, 1964). Like IDU, TFT would go on to be employed for the
topicaltreatmentofHSVkeratitis.
In1964,PrivatdeGarilheanddeRudderdescribedtheantiviralactivity
ofadeninearabinoside(ara-A)againstHSV(PrivatdeGarilhe&deRudder,
1964).ThisobservationwascorroboratedbySchabel(1968)and,underthe
guidanceofWhitley,ara-A(nowalsocalledvidarabine)becamethefirstant-
iviralusedsystemicallyforthetreatmentofherpesvirusinfections,particu-
larlyherpeszoster(Whitley,Ch’ien,Dolin,Galasso,&Alford,1976).While
vidarabineisnolongerprescribed,itpavedthewayfortheuseofacyclovir
in the treatment of (herpes) virus infections.
Alsoin1964,1-adamantanamine(amantadine)wasfoundtobeaninhib-
itorofinfluenzaAvirusinvitro(cellculture)andinvivo(mice)(Daviesetal.,
1964). Although amantadine was approved for the treatment of influenza
A virus infections, it has never been employed routinely for this condition
becauseoftherapiddevelopmentofresistancetothisagent(forareviewof
influenza virus inhibitors, see De Clercq, 2006). Currently, influenza virus
infections are treated with neuraminidase inhibitors, such as zanamivir,
oseltamivir, peramivir, and laninamivir.
Ribavirin (Virazole) was first identified as a broad-spectrum antiviral
agentbySidwellandhiscolleaguesin1972(Sidwelletal.,1972).Although
atonetimeribavirinwasadvocatedforthetherapyofarenavirusinfections,
suchasLassafever(McCormicketal.,1986),foralongperioditwasadrug
lookingforadisease.Eventually,itfoundits“niche”asanadjunctivetreat-
ment for hepatitis C virus (HCV), and for the past decade, in combination
withpegylatedinterferonithasbeenthestandardofcare.However,thedays
ix
x Preface
of ribavirin and peg-IFN appear numbered, given the development of
direct-acting antivirals (DAAs) that have proven highly effective as treat-
ment options for hepatitis C (De Clercq, 2012).
In April 1978, the first selective antiviral agent, 9-(2-hydro-
xyethoxymethyl)guanine(acyclovir)(Schaefferetal.,1978)wasintroduced.
Asapreview,Elionpublishedafewmonthsearlier(Elionetal.,1977)that
theselectivityofacycloviragainstherpesviruses,HSVinparticular,isdueto
its phosphorylation by the HSV-encoded thymidine kinase. As of today,
acyclovir is the gold standard for the treatment of HSV-1 and HSV-2
infections.
A few months after acyclovir was launched, another acyclic nucleoside
analogue, (S)-9-(2,3-dihydroxypropyl)adenine (DHPA) was reported that,
unlike the selective antiherpesvirus activity of acyclovir, displayed a broad
range of antiviral effects (De Clercq, Descamps, De Somer, & Holy´,
1978). Emerging from DHPA, and the known antiviral activity of
phosphonoacetic acid, was the design of a new class of compounds, the
prototype being (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine
[(S)-HPMPA] (De Clercq et al., 1986). Starting from (S)-HPMPA, which
was never commercialized, a new class of antiviral compounds emerged.
Collectively, this class is referred to as the acyclic nucleoside phosphonates
(ANPs) (De Clercq & Holy´, 2005). Three of these compounds, cidofovir,
adefovir, and tenofovir, are currently marketed, with tenofovir being
included in different fixed-dose combinations.
Inthe1980s,therewereonlyafewantiviralcompoundsavailableinthe
physicians’armamentarium,includingacyclovir.Asof2013,thenumberof
antiviral drugs available for prescription has grown to around 50, half of
which are employed for the treatment of AIDS, a condition that was not
yet recognized in 1980. After the causative agent of AIDS was identified
in 1983, an avalanche of drugs was developed for the treatment of AIDS,
at a pace of almost one compound per year.
SomeofthecompoundsusedforthetreatmentofHIVinfectionarealso
used for the management of chronic hepatitis B virus (HBV) infection, a
condition that globally has a 10-fold higher incidence than HIV infection.
ForthetreatmentofHCVinfection,avirusthatuntilitsidentificationinthe
1989 was classified as non-A non-B, a host of new compounds was devel-
oped. These agents, termed DAAs, have appeared in rapid succession over
thepastfewyears.TheDAAs(DeClercq,2012)arepoisedtorevolutionize
thetreatmentofHCVwhichhasforthelastdecadebeendominatedbythe
combined administration of pegylated interferon with ribavirin.
Preface xi
Asdetailedinthistext,thestrategiescurrentlyused,and/orconsidered,
for the treatment of virus infections, are focused on
1. HIV [E. De Clercq(reverse transcriptase inhibitors and protease inhib-
itors),E.DeClercq(acyclicnucleosidephosphonates),andY.Pommier
(integrase inhibitors)],
2. HCV [J.M. Pawlotsky (standard of care) and M.J. Sofia (nucleo(s)tide
polymerase inhibitors)],
3. HBV[S.J.Hadziyannis,D.Vassilopoulos,andE.Hadziyannis(manage-
ment of HBV infection)],
4. HSV [A. Vere Hodge and H.J. Field (helicase/primase inhibitors)],
5. VZV [G. Andrei and R. Snoeck (VZV inhibitors)],
6. influenzavirus[E.vanderVries,M.Schutten,P.Fraaij,C.Boucher,and
Osterhaus (anti-influenza virus agents)].
Giventherapidadvancesmadeinthedevelopmentofantiviraldrugs,thisisa
particularlyappropriatetimeforareviewofthisprogressanditsimplications
for the future of this uniquely productive field.
ERIK DE CLERCQ
REFERENCES
Davies, W. L., Grunert, R. R., Haff, R. F., McGahen, J. W., Neumayer, E. M.,
Paulshock, M., et al. (1964). Antiviral activity of 1-adamantanamine (amantadine).
Science,144,862–863.
DeClercq,E.(2006).AntiviralagentsactiveagainstinfluenzaAviruses.NatureReviews.Drug
Discovery,5,1015–1025.
DeClercq,E.(2009).Lookingbackin2009atthedawningofantiviraltherapynow50years
ago:Anhistoricalperspective.AdvancesinVirusResearch,73,1–53.
DeClercq,E.(2012).Theraceforinterferon-freeHCVtherapies:Asnapshotbythespring
of2012.ReviewsinMedicalVirology,22,392–411.
DeClercq,E.,Descamps,J.,DeSomer,P.,&Holy´,A.(1978).(S)-9-(2,3-Dihydroxypropyl)
adenine:Analiphaticnucleosideanalogwithbroad-spectrumantiviralactivity.Science,
200,563–565.
DeClercq,E.,&Holy´,A.(2005).Acyclicnucleosidephosphonates:Akeyclassofantiviral
drugs.NatureReviews.DrugDiscovery,4,928–940.
DeClercq,E.,Holy´,A.,Rosenberg,I.,Sakuma,T.,Balzarini,J.,&Maudgal,P.C.(1986).
Anovelselectivebroad-spectrumanti-DNAvirusagent.Nature,323,464–467.
Elion,G.B.,Furman,P.A.,Fyfe,J.A.,deMiranda,P.,Beauchamp,L.,&Schaeffer,H.J.
(1977).Selectivityofactionofanantiherpeticagent,9-(2-hydroxyethoxymethyl)gua-
nine. Proceedings of the National Academy of Sciences of the United States of America, 74,
5716–5720.
Field,H.J.,&DeClercq,E.(2004).Antiviraldrugs—Ashorthistoryoftheirdiscoveryand
development.MicrobiologyToday,31,58–61.
Fleming, A. (1929). On the antibacterial action of cultures of a penicillium, with special
reference to their use in the isolation of B. influenzae. British Journal of Experimental
Pathology,10,226–236.
xii Preface
Herrmann,E.C.,Jr.(1961).PlaqueinhibitiontestfordetectionofspecificinhibitorsofDNA
containing viruses. Proceedings of the Society for Experimental Biology and Medicine, 107,
142–145.
Kaufman,H.E.(1962).Clinicalcureofherpessimplexkeratitisby5-iodo-2’-deoxyuridine.
ProceedingsoftheSocietyforExperimentalBiologyandMedicine,109,251–252.
Kaufman, H. E., & Heidelberger, C. (1964). Therapeutic antiviral action of
5-trifluoromethyl-2’-deoxyuridineinherpessimplexkeratitis.Science,145,585–586.
McCormick,J.B.,King,I.J.,Webb,P.A.,Scribner,C.L.,Craven,R.B.,Johnson,K.M.,
et al. (1986). Lassa fever. Effective therapy with ribavirin. The New England Journal of
Medicine,314,20–26.
PrivatdeGarilhe,M.,&deRudder,J.(1964).Effetdedeuxnucle´osidesdel’arabinosesurla
multiplicationdesvirusdel’herpe`setdelavaccineenculturecellulaire.ComptesRendus
del’Acade´miedesSciences,259,2725–2728.
Prusoff,W.H.(1959).Synthesisandbiologicalactivitiesofiododeoxyuridine,ananalogof
thymidine.BiochimicaetBiophysicaActa,32,295–296.
Schabel,F.M.,Jr.(1968).Theantiviralactivityof9-b-D-arabinofuranosyladenine(Ara-A).
Chemotherapy,13,321–338.
Schaeffer,H.J.,Beauchamp,L.,deMiranda,P.,Elion,G.B.,Bauer,D.J.,&Collins,P.
(1978).9-(2-Hydroxyethoxymethyl)guanineactivityagainstvirusesoftheherpesgroup.
Nature,272,583–585.
Sidwell, R. W., Huffman, J. H., Khare, G. P., Allen, L. B., Witkowski, J. T., &
Robins, R. K. (1972). Broad-spectrum antiviral activity of virazole: 1-b-
D-Ribofuranosyl-1,2,4-triazole-3-carboxamide.Science,177,705–706.
Whitley,R.J.,Ch’ien,L.T.,Dolin,R.,Galasso,G.J.,&Alford,C.A.,Jr.(1976).Adenine
arabinosidetherapyofherpeszosterintheimmunosuppressed.NIAIDcollaborativeant-
iviralstudy.TheNewEnglandJournalofMedicine,294,1193–1199.
CONTRIBUTORS
G.Andrei
DepartmentofMicrobiologyandImmunology,LaboratoryofVirologyandChemotherapy,
RegaInstituteforMedicalResearch,KULeuven,Leuven,Belgium
CharlesBoucher
ViroscienceLab,ErasmusMedicalCentre,Rotterdam,TheNetherlands
ErikDeClercq
RegaInstituteforMedicalResearch,KULeuven,Leuven,Belgium
HughJ.Field
DirectorofStudiesinMedicalandVeterinarySciences,Queens’College,Cambridge,
UnitedKingdom
PieterFraaij
ViroscienceLab,ErasmusMedicalCentre,Rotterdam,TheNetherlands
EmiliaHadziyannis
SecondAcademicDepartmentofMedicineatHippokrationHospital,Nationaland
KapodistrianUniversityofAthens,Athens,Greece
StephanosJ.Hadziyannis
DepartmentofMedicineandHepatology,HenryDunantHospital,andMolecularBiology
LaboratoryoftheLiverUnitattheEvgenidionHospital,NationalandKapodistrian
UniversityofAthens,Athens,Greece
ChristopheMarchand
LaboratoryofMolecularPharmacology,CenterforCancerResearch,NationalCancer
Institute,NationalInstitutesofHealth,Bethesda,Maryland,USA
MathieuMe´tifiot
LaboratoryofMolecularPharmacology,CenterforCancerResearch,NationalCancer
Institute,NationalInstitutesofHealth,Bethesda,Maryland,USA
AlbertOsterhaus
ViroscienceLab,ErasmusMedicalCentre,Rotterdam,TheNetherlands
Jean-MichelPawlotsky
NationalReferenceCenterforViralHepatitisB,CandD,DepartmentofVirology,Hoˆpital
HenriMondor,Universite´ Paris-Est,andINSERMU955,Cre´teil,France
YvesPommier
LaboratoryofMolecularPharmacology,CenterforCancerResearch,NationalCancer
Institute,NationalInstitutesofHealth,Bethesda,Maryland,USA
MartinSchutten
ViroscienceLab,ErasmusMedicalCentre,Rotterdam,TheNetherlands
xiii
xiv Contributors
R.Snoeck
DepartmentofMicrobiologyandImmunology,LaboratoryofVirologyandChemotherapy,
RegaInstituteforMedicalResearch,KULeuven,Leuven,Belgium
MichaelJ.Sofia
OnCoreBiopharma,Inc.,andTheInstituteforHepatitisandVirusResearch(Pennsylvania
CommonwealthInstitute),Doylestown,Pennsylvania,USA
ErhardvanderVries
ViroscienceLab,ErasmusMedicalCentre,Rotterdam,TheNetherlands
DimitriosVassilopoulos
SecondAcademicDepartmentofMedicineatHippokrationHospital,Nationaland
KapodistrianUniversityofAthens,Athens,Greece
R.AnthonyVereHodge
VereHodgeAntiviralsLtd.,Surrey,UnitedKingdom
CHAPTER ONE
Antiviral Agents for Herpes
Simplex Virus
R. Anthony Vere Hodge*, Hugh J. Field†,1
*
VereHodgeAntiviralsLtd.,Surrey,UnitedKingdom
†DirectorofStudiesinMedicalandVeterinarySciences,Queens’College,Cambridge,UnitedKingdom
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. Introduction 3
1.1 TheHerpesviridae 3
1.2 RarerformsofHSVdisease 4
2. HistoricalOverview:TherapiesforHSVInfections 5
2.1 Earlyprogresstowardhighlyselectiveandeffectiveantivirals 5
2.2 ACVandPCV:Preclinicalevaluations 8
2.3 ACV,PCV,andtheirprodrugs:Clinicalstudies 14
3. ClinicalExperiencewithACV,VACV,andFCVThroughTwoDecades 19
3.1 Clinicalbenefit 19
3.2 NewopportunitiesforFCVandVACV? 20
4. AntiviralDrugResistance 22
4.1 Introduction 22
4.2 Drug-resistantstrainstestedinHSVlaboratoryanimalinfectionmodels 23
4.3 HSVdrugresistanceinophthalmicinfections 23
4.4 Drugresistanceinimmunocompromisedpatients 24
4.5 Conceptofgeneticbarrier 24
5. NovelApproachestoHSVChemotherapy 26
5.1 Nucleosideanaloguesincombinationwithanti-inflammatorycompounds 26
5.2 Helicase–primase:AnewselectivevirustargetforHSV 26
5.3 TKbypass 28
6. ProspectsforNovelAntiviralCompoundsandVaccines 29
6.1 Difficultiesfacingnovelcompounds 29
6.2 LackofprogressinthecontrolofHSVbymeansofimmunization 30
7. Conclusion 31
ConflictofInterest 33
References 34
Abstract
Thisreviewstartswithabriefdescriptionofherpessimplexvirustypes1and2(HSV-1
andHSV-2),theclinicaldiseasestheycause,andthecontinuingclinicalneedforantiviral
AdvancesinPharmacology,Volume67 #2013ElsevierInc. 1
ISSN1054-3589 Allrightsreserved.
http://dx.doi.org/10.1016/B978-0-12-405880-4.00001-9
2 R.AnthonyVereHodgeandHughJ.Field
chemotherapy.Ahistoricaloverviewdescribestheprogressfromtheearly,rathertoxic
antiviralstoacyclovir(ACV)whichledthewayforitsprodrug,valacyclovir,topenciclovir
anditsprodrug,famciclovir(FCV).ThesecompoundshavebeenthemainstayofHSV
therapyfortwodecadesandhaveestablishedaremarkablesafetyrecord.Thisreview
focusesonthesecompounds,thepreclinicalstudieswhichrevealpotentiallyimportant
differences,theclinicaltrials,andtheclinicalexperiencethroughtwodecades.Some
possibleareasforfurtherinvestigationaresuggested.
Thefocusshiftstonewapproachesandnovelcompounds,inparticular,thecom-
binationofACVwithhydrocortisone,knownasME609orzoviraxduo,anHSVhelicase–
primase inhibitor, pritelivir (AIC316), and CMX001, the cidofovir prodrug for treating
resistant HSV infection in immunocompromised patients. Letermovir has established
that the human cytomegalovirus terminase enzyme is a valid target and that similar
compoundscouldbesoughtforHSV.Wediscussthedifficultiesfacingtheprogression
ofnewcompounds.
Inourconcludingremarks,wesummarizethepresentsituationincludingadiscus-
siononthereclassificationofFCVfromprescription-onlytopharmacist-controlledfor
herpeslabialisinNewZealandin2010;shouldthisberepeatedmorewidely?Wecon-
cludethatHSVresearchisemergingfromaquiescentphase.
ABBREVIATIONS
ACV acycloviroraciclovir
AD Alzheimer’sdisease
AIC316 AiCurishelicase–primaseinhibitor(BAY57-1293orpritelivir)
BAY57-1293 AiCurishelicase–primaseinhibitor(AIC316orpritelivir)
BVDU bromovinyldeoxyuridine,brivudin
CDC CentersforDiseaseControlandPrevention(USA)
CDV cidofovir
CMX001 hexadecyloxypropyl-cidofovir
DNApol DNApolymerase
FCV famciclovir
FDA FoodandDrugAdministration(USA)
FOS foscarnet(phosphonoformicacid)
H2G omaciclovir
HK herpeskeratitis
HPI helicase–primaseinhibitor
HSV herpessimplexvirus
IDU idoxuridine(5-iodo-20-deoxyuridine)
i.v. intravenous
ME609 zoviraxduo
PCV penciclovir
PK pharmacokinetics
T1/2 half-life
TFT trifluorothymidine
TK thymidinekinase
VACV valacyclovir
VZV varicella-zostervirus
wt wildtype
Anti-HSVAgents 3
1. INTRODUCTION
1.1. The Herpesviridae
Herpessimplex virus (HSV) is a member of the alphaherpesvirus subgroup
oftheHerpesviridae.Thisisafamilyoflarge,double-strandedDNAviruses
whicharewidelydistributedamonganimalsandman.Thevariousmembers
ofthisfamilyhaveevolvedcomplexrelationshipswiththeirparticularhosts
over tens of millionsof years (Davison, 2007). A notable feature of HSVis
thatinfectionsarelifelong.Followingprimaryinfectionwhichmay,ormay
not,beaccompaniedbyclinicalsignsofdisease,thevirustypicallyestablishes
a latent infection in the neurons of the peripheral nervous system. During
periodsoflatency,noinfectiousvirusisdetectedinthehostandthequies-
centvirusprovidesaspecialchallengeforantiviralchemotherapy.Antiviral
compounds,whichinhibit virus functionsinvolved inthe virusreplication
cycle, are inactive during the latent phase, and to date, no therapy has
succeededineliminatinglatentHSV.LatentHSVmayreactivatefromtime
to time and recurrence of infectious virus, delivered via the sensory nerve
supplytotheskin,givesthepossibilityoftransmissiontoanewsusceptible
host.Often(butnotinallcases),recurrencesofinfectiousvirusareaccom-
paniedbytheclassicsignsofrecurrentherpes.Thesearetypicallylesionsat
or near the mucocutaneous junctions, for example, on or near the lip or
genitalia.
1.1.1 HSV-1 and HSV-2 are closely related viruses
Genetic analysis reveals that HSV comprises two closely related viruses:
HSV-1andHSV-2.Theformerismostfrequentlyassociatedwithrecurrent
orallesions(herpeslabialisknownascoldsores)andHSV-2withrecurrent
genital lesions (herpes genitalis or genital herpes). Recent surveys suggest
that seropositivity for HSV in Europe varies widely by country but
approximately 50–80% of adults are infected with HSV-1 and a lesser
proportion(4–24%)withHSV-2(Pebodyetal.,2004).Itwasofinterestthat
this survey showed no protective effect of prior infection with HSV-1 in
susceptibilitytoHSV-2althoughtheclinicalsignsmaybelessinsomecases.
Inrecentyears,thereappearstohavebeenanincreaseintheseroprevalence
of HSV-2. Furthermore, there appears to be an increasing prevalence of
isolatesofHSV-1fromgenitallesionssuggestingachangeinsexualpractices
(Gilbert et al., 2011). The frequency of recurrent lesions varies among
seropositive individuals for both types of virus from never or very rare to