Paxlovid and Molnupiravir What Are The Differences.pdf

On November 4, 2021, the Medicines and Healthcare Products Regulatory Agency (MHRA) granted marketing approval for Molnupiravir (trade name: Lagevrio), an oral COVID-19 drug co-developed by Merck and Ridgeback, for the treatment of patients with mild to moderate COVID-19. This is the first oral antiviral drug approved globally for the treatment of mild to moderate COVID-19 in adults.

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PaxlovidandMolnupiravir:WhatAreThe
Differences?
OnNovember4,2021,theMedicinesandHealthcareProductsRegulatory
Agency(MHRA)grantedmarketingapprovalforMolnupiravir(tradename:
Lagevrio),anoralCOVID-19drugco-developedbyMerckandRidgeback,for
thetreatmentofpatientswithmildtomoderateCOVID-19.Thisisthefirstoral
antiviraldrugapprovedgloballyforthetreatmentofmildtomoderate
COVID-19inadults.
Clinicaldatashowedthat775patientsrecentlyinfectedwithCOVID-19were
treatedwithmolnupiravirorplacebo,respectively.Therewere7.3%
hospitalizationsandnopatientdeathsinthemolnupiravir-treatedgroupand
14.1%hospitalizationsand8deathsintheplacebogroup,p=0.0012.Therisk
ofhospitalizationanddeathwasreducedby50%inthemolnupiravir-treated
groupcomparedtotheplacebogroup.[1]
ItisimportanttonotethatMolnupiravirmustbetakenwithinfivedaysofthe
onsetofsymptomsofviralinfection,andisnoteffectiveifthepatientisalready
hospitalized.Inaddition,patientswithmildtomoderateCOVID-19taking
Molnupiravirshouldalsoincludeatleastoneofthefollowingriskfactors:e.g.,
obesity,oldage,diabetes,orheartdisease.
Justonedaylater,onNovember5,2021,Pfizermadeanannouncement
thatPAXLOVID(PF-07321332;ritonavir),Pfizer'sproprietaryCOVID-19oral
drug,mettheprimarystudyendpoint.Theriskofdeathandhospitalizationwas
reducedby89%inthePAXLOVIDtreatmentgroupcomparedtotheplacebo
controlgroup.
ThisannouncementisbasedonaninterimanalysisofthePhase2/3EPIC-HR
(EvaluationofProteaseInhibitionforCOVID-19inHigh-RiskPatients)
randomized,double-blindstudyofnon-hospitalizedadultpatientswith
COVID-19,whoareathighriskofprogressingtosevereillness.
Thescheduledinterimanalysisshowedthat0.8%ofpatientstreatedwith
PAXLOVIDwerehospitalizedwithinday28afterrandomizationgrouping
(3/389hospitalizations,nopatientdeaths),comparedwith7.0%ofpatients
treatedwithplacebowhowerehospitalizedordied(27/385hospitalizations,7
deaths).Thestatisticalsignificanceoftheseresultswashigh(p<0.0001).
AsimilarreductioninhospitalizationsordeathsassociatedwithCOVID-19
wasobservedinpatientstreatedwithPAXLOVIDwithinfivedaysofsymptom

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onset.1.0%ofpatientsrandomizedtoPAXLOVIDwerehospitalizedwithinday
28(6/607hospitalizations,nodeaths)comparedto6.7%ofpatientstreated
withplacebo(41/612hospitalizations,10subsequentdeaths),whichwas
highlystatisticallysignificant(p<0.0001).Intheentirestudypopulation,no
deathswerereportedinpatientstreatedwithPAXLOVIDthroughday28.In
contrast,therewere10(1.6%)deathsinpatientstakingplacebo[2].
Fromtheabovedata,wecanroughlyseethatPfizer'sPaxlovidseemstohave
betterefficacythanMerck'sMolnupiravir.Soarethereanydifferencesinthe
developmentmechanismofthesetwodrugs?
HowTheCoronavirusInfectsCells?
Coronaviruses(SARS-CoV-2)areenvelopedvirusesthatcontainapositive,
single-strandedRNAgenome,whichispackagedwithinacapsid.Thecapsid
consistsofthenucleocapsidproteinNandthisisfurthersurroundedbya
membrane,thatcontainsthreeproteins:themembraneprotein(M)andthe
envelopeprotein(E),whichareinvolvedinthevirusbuddingprocess,andthe
spikeglycoprotein(S),whichisakeyplayerinbindinghostreceptorand
mediatingmembranefusionandvirusentryintohostcells.
StructureofCOVID-19Virus
Following,let'susfindthemechanismofCOVID-19entryandviralreplication
andviralRNApackinginthehumancell[3].

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(a)TheS-proteinonthesurfaceofthevirusbindstotheACE2
(angiotensin-convertingenzyme2)receptorinhumanlungcells,allowingentry
ofthecoronavirusintohumancellsthroughendocytosis(membranefusion).
(b)Afterthevirusentersthecytoplasm,theproteasomeofthehumancell
hydrolyzestheS-protein,furtheractivatingmembranefusioninvivo.
(c)Theproteasomehydrolyzestheviralnucleocapsidproteinandtheviral
geneticmaterial,single-strandedRNA,iscompletelyreleasedintothe
cytoplasm.
(d)RNAistranslatedintopolypeptidechainswiththehelpofribosomesand
hydrolyzedintoRNA-dependentRNApolymerase(RdRp)by3CLproenzyme
(3(a)RdRpusesthegenomeasatemplatetogeneratefull-length
negative-senseRNA,whichsubsequentlyservesasatemplatetogenerate
additionalfull-lengthgenomes.
(e)Viralmembraneproteins,S-proteinsandenvelopeproteinsare
synthesizedinthecytoplasmandtheninsertedintotheendoplasmicreticulum
andtransferredtotheGolgiintermediatecompartmentoftheendoplasmic
reticulum.
(f)Inthecytoplasm,nucleocapsidsareformedbycapsidizationofreplicating
genomesbynucleocapsidproteins,whichthenaggregatewithinthe
endoplasmicreticulum-Golgiintermediatecompartmentmembraneto
self-assembleintonewviralparticles.
(g)Finally,thenewviralparticlesaretransportedtothecellmembranevia
smooth-walledvesicles,whicharethensecretedviaexocytosisandthus
exportedfromtheinfectedcell,therebyinfectingothercells.Atthesametime,
thevirusgeneratespressureontheendoplasmicreticulumeventuallyleading
tocelldeath.

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TheschematicdiagramofthemechanismofCOVID-19entryandviral
replicationandviralRNApackinginthehumancell.
TreatmentStrategiesforCOVID-19
Fromtheprocessofentryofthecoronavirusintohumancellsandsome
historicalexperiencewithcoronaviruses,wecanbroadlyderivethefollowing
waystoblockthereplicationofthevirusandtreatCOVID-19.
(1)DirectattackontheS-proteintargetoftheviruswiththehelpofmonoclonal
antibodiesorplasmafromrecoveredpatients,whichisalsothemechanismof
actionofthevaccine,keepingtheviruscompletelyoutofhumancells.
(2)Atthecellularlevel,thetransmembraneproteaseserine2(TMPRSS2)
preemptivelycontactstheS-proteinofcoronavirusesandpromotesviralentry
andinfection,soTMPRSS2wouldbeapotentialtargetfordrugdevelopment
toinhibitCOVID-19.TMPRSS2inhibitors,suchascamostatmesylate,are
consideredtobepotentialantiviralagentsagainstCOVID-19.Severalclinical
trialsofcamostatmesylateforthetreatmentofCOVID-19havebeencarried
out.Theresultsofonerandomizedcontrolledtrialshowednoimprovementin
clinicals[4].
(3)Chloroquine(CQ)andhydroxychloroquine(HCQ)havedemonstrated
positiveresultsindicatingapotentialantiviralroleagainstSARS-CoV-2（HCQ
ispreferredduetoitshigherwatersolubility,lowertoxicityandalsofeasibility
forprolongedusewithincreasedtolerance）.Itsmechanismofaction(MOA)
includestheinterferenceintheendocyticpathway,blockadeofsialicacid
receptors,restrictionofpHmediatedspike(S)proteincleavageatthe

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angiotensin-convertingenzyme2(ACE2)bindingsiteandpreventionof
cytokinestorm.Unfortunately,itsadverseeffectslikegastrointestinal
complications,retinopathyandQTintervalprolongationareevidentintreated
COVID-19patients.ButthereisalackofqualityevidencetodemonstrateCQ
andHCQareeffectiveinthetreatmentofCOVID-19.
(4)Theviral3-chymotrypsin-likecysteineprotease(3CLpro),playingpivotal
rolesincoronavirusreplicationandpolyproteinprocessing,isessentialforits
lifecycle.Therefore,inhibiting3CLproenzymeisalsoanimportantwayto
blockviralreplication.TheHIVinhibitorritonavir/lopinavircaninhibitthe
3CLproenzymeactionofCOVID-19,andtheoral
drugPF-07321332developedbyPfizerhasasimilarmechanism.Theaddition
ofritonavirreducestherateofmetabolismofPF-07321332byhumancells
andenhancestherapeuticconcentrations.
(5)RNA-dependentRNApolymerase(RdRp)cansynthesizenewviralRNA
usingviralsingle-strandedRNAasatemplate,therefore,viralreplicationcan
alsobeblockedbyinhibitingtheactionofRdRp.Remdesivirisa
phosphoramidateprodrugthatismetabolizedincellstoyieldanactiveNTP
analog21thatwerefertoasremdesivirtriphosphate(RTP).RdRpcanbe
insertedintotheRNAstrandbeingextendedusingRTPasasubstrate,after
whichthereplicationprocessofRdRpisblocked.Thenucleosideanalogue
RemdesivircanavoidproofreadingcorrectionduringRNAreplicationbecause
itsincorporationdoesnotimmediatelyterminatetheextension,butwillblock
RdRponlyaftertheadditionofthreenucleotides[5].
(6)TheoraldrugMolnupiravir,developedbyMerckasasubstratealternative
tocytidine/uridinetriphosphate,canincorporateseitherAorGwhenRdRp
usesviralRNAasatemplateforreplication,resultinginamutated
RNA.StructuralanalysisofRdRp-RNAcomplexescontainingmutated
productsshowedthatMolnupiravircouldformstablebasepairswitheitherG
orAintheRdRpactivecenter,whichexplainshowthepolymerasecould
escapeproofreadingandsynthesizemutatedRNA.UnlikeRemdesivir,
MolnupiravirdoesnotblocktheactionofRdRp,butreducesCOVID-19activity
byproducingmutantviralRNAbyamechanismsimilartothatofFavipiravir
[6].

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PaxlovidandMolnupiravir:DifferenceInMechanismofAction
Inprinciple,Pfizer'soraldrugPAXLOVIDdirectlyinhibitstheactionof
COVID-19RNApolymerase,blockingtheprocessofviralreplication;while
Mercer'soraldrugMolnupiravirdoesnotblockthereplicationofRNA,but
generatesmutatedgeneticmaterialbyreplacingCandGbaseswithfake
nucleosideanalogues.However,itisstillworthinvestigatingwhetherthe
mutatedRNAisstillvirulent.
Conclusion
Vaccines,Remdesivir,MolnupiravirandPAXLOVID,despitetheirdifferent
mechanismsofdevelopment,areallbasedonadeepunderstandingofviral
structureandphysiologicalprocesses,andareeffectiveweaponsinour
responsetoCOVID-19.DifferentR&Dstrategiesmayleadtodifferentresults.
Asofnow,Pfizer'soraldrugworksbetterthanMerckSharp&Dohme's,or
evenotherdrugs,whileCamostatMesylatehasbeenproventobeineffective
inCOVID-19patients,butnoneofthiscandenytheexplorationandefforts
madebythescientistsbehindit.
HuatengPharmacanofferpharmaceuticalintermediatecontract
manufacturingservices.Withcomprehensivetechnicalexpertiseandcurrent
GMPfacilitiesinChina,wecanprovidecustomsynthesisforR&Dand
commercialscaleupofthesePaxlovidintermediates.
▶CASNO.67911-21-1|Caronicanhydride
▶CASNO.194421-56-2|6,6-Dimethyl-3-Azabicyclo[3.1.0]hexane-2,4-dione
▶CASNO.565456-77-1|(1R,2S,5S)-Methyl
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylatehydrochloride
▶CASNO.943516-54-9|6,6-Dimethyl-3-azabicyclo[3.1.0]hexane
References:
[1]Molnupiravir:WhatistheCOVID-19pillandhowdoesit
work?,https://www.sciencefocus.com/news/molnupiravir-covid-pill/
[2]Pfizer’sNovelCOVID-19OralAntiviralTreatmentCandidateReducedRisk
ofHospitalizationorDeathby89%inInterimAnalysisofPhase2/3EPIC-HR
Study,https://www.pfizer.com/news/press-release/press-release-detail/pfizers
-novel-covid-19-oral-antiviral-treatment-candidate
[3]BoopathiS,PomaAB,KolandaivelP.Novel2019coronavirusstructure,
mechanismofaction,antiviraldrugpromisesandruleoutagainstits
treatment.JBiomolStructDyn.2021;39(9):3409-3418.
doi:10.1080/07391102.2020.1758788

8. HuatengPharma https://us.huatengsci.com
[4]Gunst,J.D.,Staerke,N.B.,Pahus,M.H.,Kristensen,L.H.,Bodilsen,J.,
Lohse,N.,etal.(2021).EfficacyoftheTMPRSS2InhibitorCamostatMesilate
inPatientsHospitalizedwithCovid-19-ADouble-BlindRandomizedControlled
Trial.EClinicalMedicine35,100849.doi:10.1016/j.eclinm.2021.100849
[5]Kokic,G.,Hillen,H.S.,Tegunov,D.etal.MechanismofSARS-CoV-2
polymerasestallingbyremdesivir.NatCommun12,279
(2021).https://doi.org/10.1038/s41467-020-20542-0
[6]Kabinger,F.,Stiller,C.,Schmitzová,J.etal.Mechanismof
molnupiravir-inducedSARS-CoV-2mutagenesis.NatStructMol
Biol28,740–746(2021).https://doi.org/10.1038/s41594-021-00651-0
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