Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates

Abstract

Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor -α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively , will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host-pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates.

Full text

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Molecules2021,26,2917.https://doi.org/10.3390/molecules26102917www.mdpi.com/journal/molecules
Review
TargetingMultipleSignalTransductionPathways
ofSARS‐CoV‐2:ApproachestoCOVID‐19
TherapeuticCandidates
SajadFakhri
1,†
,ZeinabNouri
2,†
,SeyedZachariahMoradi
1,3
,EsraKüpeliAkkol
4
,SanaPiri
1
,
EduardoSobarzo‐Sánchez
5,6,
*,MohammadHoseinFarzaei
7,
*andJavierEcheverría
8,
*

1
PharmaceuticalSciencesResearchCenter,HealthInstitute,KermanshahUniversityofMedicalSciences,
Kermanshah6734667149,Iran;pharmacy.sajad@yahoo.com(S.F.);zmoradi@kums.ac.ir(S.Z.M.);
sanapiri@ymail.com(S.P.)
2
StudentResearchCommittee,KermanshahUniversityofMedicalSciences,Kermanshah6714415153,Iran;
zeinab7641@yahoo.com
3
MedicalBiologyResearchCenter,HealthTechnologyInstitute,KermanshahUniversityofMedicalSciences,
Kermanshah6734667149,Iran
4
DepartmentofPharmacognosy,FacultyofPharmacy,GaziUniversity,Etiler,06330Ankara,Turkey;
esrak@gazi.edu.tr
5
InstitutodeInvestigaciónyPostgrado,FacultaddeCienciasdelaSalud,UniversidadCentraldeChile,
Santiago8330507,Chile

6
DepartmentofOrganicChemistry,FacultyofPharmacy,UniversityofSantiagodeCompostela,
15782SantiagodeCompostela,Spain

7
MedicalTechnologyResearchCenter,HealthTechnologyInstitute,KermanshahUniversityofMedical
Sciences,Kermanshah6734667149,Iran
8
DepartamentodeCienciasdelAmbiente,FacultaddeQuímicayBiología,
UniversidaddeSantiagodeChile,Santiago9170022,Chile
*Correspondence:e.sobarzo@usc.es(E.S.‐S.);mh.farzaei@gmail.com(M.H.F.);
javier.echeverriam@usach.cl(J.E.)
†Theauthorshavecontributedequallytothisreview.
Abstract:Duetothecomplicatedpathogenicpathwaysofcoronavirusdisease2019(COVID‐19),
relatedmedicinaltherapieshaveremainedaclinicalchallenge.COVID‐19highlightstheurgent
needtodevelopmechanisticpathogenicpathwaysandeffectiveagentsforpreventing/treatingfu‐
tureepidemics.Asaresult,thedestructivepathwaysofCOVID‐19areinthelinewithclinicalsymp‐
tomsinducedbysevereacutecoronarysyndrome(SARS),includinglungfailureandpneumonia.
Accordingly,revealingtheexactsignalingpathways,includinginflammation,oxidativestress,
apoptosis,andautophagy,aswellasrelativerepresentativemediatorssuchastumornecrosisfac‐
tor‐α(TNF‐α),nuclearfactorerythroid2‐relatedfactor2(Nrf2),Bax/caspases,andBeclin/LC3,re‐
spectively,willpavetheroadforcombatingCOVID‐19.Prevailinghostfactorsandmultiplesteps
ofSARS‐CoV‐2attachment/entry,replication,andassembly/releasewouldbehopefulstrategies
againstCOVID‐19.Thisisacomprehensivereviewofthedestructivesignalingpathwaysandhost–
pathogeninteractionofSARS‐CoV‐2,aswellasrelatedtherapeutictargetsandtreatmentstrategies,
includingpotentialnaturalproducts‐basedcandidates.
Keywords:coronavirus;SARS‐CoV‐2;COVID‐19;signalingpathway;inflammation;oxidative
stress;apoptosis;autophagy;naturalproducts

1.Introduction
Asaglobalpandemic,anoutbreakofnovelcoronavirus,namedsevereacuterespir‐
atorysyndromecoronavirus2(SARS‐CoV‐2),causedthecoronavirusdisease2019
(COVID‐19).Ithasbeenaseriousleadingcauseofmorbidityandmortalityworldwide
Citation:Fakhri,S.;Nouri,Z.;
Moradi,S.Z.;Akkol,E.K.;Piri,S.;
Sobarzo‐Sánchez,E.;Farzaei,M.H.;
Echeverría,J.TargetingMultiple
SignalTransductionPathwaysof
SARS‐CoV‐2:Approachesto
COVID‐19TherapeuticCandidates.
M
olecules2021,26,2917.https://
doi.org/10.3390/molecules26102917
AcademicEditor:Kyoko
Nakagawa‐Goto
Received:18March2021
Accepted:11May2021
Published:14May2021
Publisher’sNote:MDPIstaysneu‐
tralwithregardtojurisdictional
claimsinpublishedmapsandinstitu‐
tionalaffiliations.

Copyright:©2021bytheauthors.Li‐
censeeMDPI,Basel,Switzerland.
Thisarticleisanopenaccessarticle
distributedunderthetermsandcon‐
ditionsoftheCreativeCommonsAt‐
tribution(CCBY)license(https://cre‐
ativecommons.org/licenses/by/4.0/).

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[1,2].Coronaviruses(CoVs)areagroupofsingle‐strandedenvelopedribonucleicacidvi‐
ruseswhichareclassifiedintofourgenera,includingα,β,γ,andδ.Inthepasttwodec‐
ades,twomembersoftheβ‐CoVswithazoonoticorigin,includingSARS‐CoVandMid‐
dleEastRespiratorySyndrome(MERS)‐CoV,causedtwoepidemicsinChinaduring
2002–2003andintheMiddleEastin2012,respectively[3–5].
TheclinicalmanifestationsofCOVID‐19mainlyencompasspneumonia‐related
symptoms,suchasfever,cough,andshortnessofbreath[6].Inseverepatients,itwould
leadtoacuterespiratorydistresssyndrome(ARDS),cardiovascular,neurological,hepatic,
renal,andgastrointestinalcomplications[7,8],whichallseemedtobecorrelatedwith
dysregulatedmechanisms.Ithasbeenwell‐establishedthattheSARS‐CoV‐2genomeis
closelyrelatedtothefirstSARS‐CoV[9].TheunderlyingmechanismsbywhichSARS‐
CoV‐2elicitsitsdetrimentaleffectsremainedunclear;however,possiblemechanismsen‐
compassinflammation,oxidativestress,apoptosis,autophagy,andtheprocessesassoci‐
atedwithvirusentryintohostcells,suchastheendocyticpathwayandangiotensin‐con‐
vertingenzyme2(ACE2)pathway[8,10–12].Asofyet,nospecificantiviraldrughasbeen
discoveredforSARS‐CoV‐2;hence,extensivestudieshavebeenignitedtofindeffective
drugsfortargetingtheaforementionedpathwaysandforcombatingCOVID‐19.Inlight
oftheoutbreak,severalnon‐specificmedicationshavebeenexploited,suchasbroad‐spec‐
trumantiviral,anti‐inflammatory,antioxidant,andantiapoptotictherapies,immunother‐
apeuticagents,antibiotics,andsupportivecaresuchassupplementaryoxygen[13–15].
Despiteadvancementsinprovidingantiviraldrugs,theirassociatedtoxicityandhighfi‐
nancialcostsareasignificanthurdleintheirclinicalapplications[16].Therefore,there
existsadireneedtodiscovernew,safe,andmoreefficacioustreatmentalternativesto
achievesuccessfulhealingtherapies.
Inrecentreviews,theroleofoxidativestress[17],inflammation[18,19],andsome
hostfactors[20]weredevelopedseparately,withnofocusonallthetherapeuticagents,
therapeutictargets,host–pathogeninteraction,anddysregulatedsignalingpathwaysin‐
volvedinthepathogenesisofSARS‐CoV‐2.Inthepresentreview,wedescribethedysreg‐
ulatedsignalingpathwaysandhost–pathogeninteractionofSARS‐CoV‐2,aswellasrel‐
ativetherapeutictargetsandtreatmentstrategies,concentratingonoxidativestress,in‐
flammation,apoptosis,autophagy,theimmunesystem,andviruslifecycle.
2.COVID‐19:GeneticsandStructure
SARS‐CoV‐2isasingle‐strandedenvelopedribonucleicacidviruswithagenome
sizeof29,903nucleotides[21].ThissinglestrandofRNAiscoveredbyaphosphorylated
capsidproteinwhich,together,bothformanucleocapsid.Phospholipidbilayersshield
thenucleocapsidandarecoatedbyspikeglycoproteinand,probably,hemagglutinin‐es‐
teraseprotein[22].Thevirusgenomeiscomprisedoftwountranslatedregions(UTRs)at
the5’and3’ends,whichconstitute265and358nucleotides,respectively,aswellas11
openreadingframes(ORFs)thatencode27structural,non‐structural,aswellasaccessory
proteins[23,24].TwooverlappingORF1aand1bcontaintwo‐thirdsofthegenomeand
encode16non‐structuralproteins(NSPs)withinthepp1abgene.Theseproteinscomprise
NSP3(papain‐like),NSP5(3C‐likeproteasedomain),NSP12(RNA‐dependentRNApol‐
ymerase),NSP13(helicase),NSP14(3′–5′exonuclease),aswellasotherNSPsthatareen‐
gagedwiththetranscriptionandreplicationoftheviralgenome[25,26].Theremaining
ORFscodestructuralproteinsincludingspikeprotein(S),envelopesprotein(E),mem‐
braneprotein(M),aswellasnucleocapsidprotein(N),andatleastsixaccessoryproteins
suchasorf3a,orf6,orf7a,orf7b,orf8,andorf10[27].Insomecases,thehemagglutininester‐
asegeneproposedtoincreasethevirusentrymediatedtoSproteinhasbeenlocatedbe‐
tweenORF1bandORFS[28].

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3.ClinicalFeaturesofCOVID‐19Disease
MostpatientsinfectedwithSARS‐CoV‐2exhibitrespiratorycomplicationssuchas
pneumoniaandARDS.ARDSisacommonleadingcauseofdeathinpatientswith
COVID‐19,whichischaracterizedbypulmonaryandinterstitialtissuedevastation[29].
ThegeneticmaterialofSARS‐CoV‐2hasbeenidentifiedincerebrospinalfluid,indicating
thatSARS‐CoV‐2candirectlyattackthecentralnervoussystem,whichcontributestosev‐
eralneurologicaldamages.Thisproceduredevelopsneurologicalcomplications,includ‐
ingheadache,encephalitis,impairedconsciousness,epilepsy,taste/smelldisorders,and
nausea/vomiting[30–32].SARS‐CoV‐2exploitsneuronalpathways,suchastheolfactory
pathwayandbloodcirculationpathway,toenterthenervoussystem[33–35].During
SARS‐CoV‐2infection,impairmentoftherespiratorygaseousexchangeleadstohypoxia
andanaerobicmetabolism,aswellasacidicconditionsinthebrain,which,inturn,partic‐
ipateincerebraledemaandocclusionofthecerebralcirculation,andsubsequentlylead
toheadacheandacutecerebrovasculardisease[36].SARS‐CoV‐2alsoexertsitsdeleteri‐
ouseffectsonthenervoussystemthroughanintracranialcytokinestorm[37].Activation
ofmacrophages,microglia,andastrocytesenhancesthereleaseofpro‐inflammatorycy‐
tokinesandprovokesnervedegenerationandtheapoptoticdeathofneuronalcells[38].
AgrowingnumberofpatientsinfectedwithSARS‐CoV‐2manifestsignsorsymptomsof
liverdysfunctionthatcanbeattributedtotherespiratorydistresssyndrome‐inducedhy‐
poxiaandthereleaseofhugecirculatingdetrimentalinflammatorymediatorswiththe
abilitytoinvadelivercells,causinghepatocytedamageandelevatedliverenzymes[39].
Additionally,thedownregulationofACE2bySARS‐CoV‐2mayenhancebloodpressure,
andtherebyelevatetheriskofintracranialhemorrhage[40].
AgrowingnumberofpatientsinfectedwithSARS‐CoV‐2manifestedsignsofliver
dysfunctionthatcanbeattributedtotherespiratorydistresssyndrome‐inducedhypoxia
andthereleaseofhugecirculatingdetrimentalinflammatorymediatorswiththeability
toinvadelivercells,causinghepatocytedamagesandelevatedliverenzymes[39].
Cardiovascularcomplicationssuchasacutemyocardialinfarction,venousthrombo‐
embolicevents,myocarditis,andheartfailuremayalsooccurinpatientswithCOVID‐19
duetodirectvirusinvasionthroughACE2,endothelialdysfunction,hypoxia,excessive
inflammatoryresponses,oxidativestress,elevatedlevelofangiotensin(Ag)II,andather‐
oscleroticplaquerupture[41,42].Besides,elevatedcardiacbiomarkers,includingtro‐
poninT,havealsobeendemonstratedtobeassociatedwithincreasedinflammatory
markers,suggestingthatmyocardialinjuryislinkedtoinflammation[43].
Gastrointestinalsymptoms,suchasvomiting,diarrhea,orabdominalpain,areother
commonclinicalmanifestationsofCOVID‐19duringtheearlyphasesofthedisease.In‐
testinaldysfunctionleadstochangesinintestinalmicrobes,therebypromotinginflamma‐
torycytokines[44].Consequently,ACE2ishighlyexpressedinthegastrointestinaltract
andSARS‐CoV‐2directlyinvadestheguttractthroughbindingwithACE2receptors.In
thisregard,ACE2isconsideredakeyregulatorofintestinalinflammationandcanen‐
hancetheriskofcolitisandothergastrointestinalsymptoms[45].
ClinicaldatahavedemonstratedthepresenceofSARS‐CoV‐2particlesinurinesam‐
plesofpatientsinfectedwithCOVID‐19[46].IthasbeenreportedthatSARS‐CoV‐2pos‐
sessesdetrimentalimpactsonkidneyfunctionandcausessigns/symptomsofacutekid‐
neyinjury[47].TheexpressionofACE2onpodocytesandtubuleepithelialcellsmakes
thekidneyahostcandidateforSARS‐CoV‐2[48].Localinflammatory/immunereaction,
directcytotoxicviraleffect,hypoxia,aswellassecondaryinfections/sepsisinducetheoc‐
currenceofendothelialdysfunction,tubularinjury,andheavyproteinuria[49].Therefore,
giventheinvolvementofhostfactorssuchasACEandrelatedcomplicationsattributed
tooxidativestress,aswellasinflammation,apoptosis,andautophagyinthecomplica‐
tionsofCOVID‐19,targetingthemisofgreatimportance.

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4.SARS‐CoV‐2Infection
SARS‐CoV‐2undergoesvariousstepsoffusion,uncoating,nucleicacidsynthesis,in‐
tegration,protease,andassembly/releasetowardsinfection;therefore,detailed
knowledgeofinfectionpathwaysiscriticaltotacklingCOVID‐19.Ithasbeenwell‐estab‐
lishedthatSARS‐CoV‐2entersthehostcellsviatwopathways,includingtheendocytic
pathwayandnon‐endosomalpathway,withthehelpofproteases(e.g.,TMPRSS2);both
contributetothereleaseofthenucleocapsidintothecytoplasm[22].Amongthosefactors,
SARS‐CoV‐2utilizestheendocyticpathwayastheprincipalmechanismforviralentry
intoseveraltypesofhostcells.TheSproteinonthesurfaceofacoronaviruscaninteract
withthereceptorandtheninvadethehostcellsthroughclathrin‐mediatedendocytosis
[11].Recentadvanceshavehighlightedthecriticalroleofsuchhostreceptors,including
ACE2,glucose‐regulatedprotein78(GRP78),clusterofdifferentiation147(CD147),and
dipeptidylpeptidase(DPP4)inviralinfection.
4.1.ACE2
Revealingthefirstphaseofviralentryintothehostcells,fusion/entrythroughfacil‐
itatingco‐receptorscouldbetargetedbyappropriatetherapeuticagents[50].Recentad‐
vanceshavehighlightedthecriticalroleofsuchhostreceptorsinviralinfection,including
ErbB1,tyrosinekinasereceptors(TKRs)[51],toll‐likereceptors(TLRs)[52],TNF‐α,ILs,
interferon(IFN)‐γ,andotherreceptorsaffectingtheimmunesystem[53].Theinvolve‐
mentofotherreceptorsrelatedtoTcellshasalsobeenshowntoplaycriticalrolesinviral
infection,suchascytotoxicT‐lymphocyteantigen4(CTLA‐4),programmeddeath1(PD‐
1),aswellasT‐cellimmunoglobulin(Ig)andmucindomain‐containingmolecule3(TIM‐
3)[54,55].
ContinuousuncoatingandnucleicacidsynthesiswiththeinvolvedenzymesofRNA
polymeraseareotherstepsinvirusreplication,includingforSARS‐CoV‐2.Viralchain
terminaseandproteaseshavealsobeenshowntobepromisingtargetsagainstCOVID‐19
complications.Asthefinalstepofviralinfection,theviralreleasecouldalsobeahopeful
targetincombatingCOVID‐19.Nowadays,hostco‐receptorshavebeenconsideredcriti‐
calagentswithundeniablerolesinstimulatingtheimmunesystemandincreasingviral
infection[56].TheanalysisofnucleicacidsequencewithinthespikeproteinsofSARS‐
CoV‐2predictedtheroleofACE2inthecellularentryofthevirus,whichwasconfirmed
byaninvitrostudy[56].
SynthesizedACE2isfoldedandN‐glycosylatedintheendoplasmicreticulum(ER)
thenpassestoGolgiapparatusforfurthermodificationsandpackagingandisthentrans‐
portedtotheplasmamembrane[57].CleavageofACE2byAdisintegrinandmetallopro‐
teinase17(ADAM17)leadstothereleaseofsolubleACE2intotheextracellularenviron‐
ment.Consequently,angiotensinreceptorI(ARI)enhancesADAM17expressionwhich,
inturn,elevatessolubleACE2,andcanthereforepreventSARS‐CoV‐2entrance[57,58].
Additionally,inresponsetoSARS‐CoV‐2,bindingviaclathrin‐mediatedendocytosisand
theinternalizationofboththevirusanditsreceptor,ACE2,occur[59].
TherateexpressionofACE2anditscleavagefromthecellmembranecontributeto
theregulationofACE2activity[60].Ithasbeenwell‐establishedthatAgII,whichmiti‐
gatesACE2expression,passesthroughtypeIIalveolar(AT2)andtypeIalveolar(AT1)‐
extracellular‐regulatedkinase(ERK)/p38mitogen‐activatedproteinkinase(MAPK)path‐
way,therebyplayingapivotalroleintheregulationofassociatedreceptors[61].Addi‐
tionally,hypoxia‐inducedfactor‐1α(HIF‐1α)enhancestheproductionofACE,which,in
turn,booststheproductionofAgII,andthenleadstoareducedlevelofACE2[62].SARS‐
CoV‐2‐induceddownregulationofACE2leadstoanaugmentationofthepro‐inflamma‐
toryfactor,AgII,andcauseslunginjury[63].TherecognizedreceptorofSARS‐CoV‐2,
ACE2,ismainlyexpressedinasmallsubsetoflungcells[64].Onlyminimalpercentages
ofmonocytes/macrophagesinthelungexpressedACE2[64].Itpresentsthepossibilityof
directcellularinfection(withnoACE2engagement)ortheexistenceofotherreceptors

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involvedinSARS‐CoV‐2entrances[65,66].Ingeneral,thecriticalroleoftherenin–angio‐
tensinsystem(RAS)hasbeenindicatedinvariouspathologicalandphysiologicalpro‐
cesses.Consequently,angiotensinogenisconvertedtoAgIbyrenin.AgIis,inturn,con‐
vertedtoAgIIthentoAg(1–7),andMasbyACE1andACE2,respectively.WhileAgII
bindstoARIandmakespathologicaloutcomes,MasbindstoMasRtoexertprotective
responsesagainstCOVID‐19[67,68].Therefore,ACE2couldplaythedouble‐edgedrole
ofbeingaco‐receptorforSARS‐CoV‐2entryandgeneratingMasforprotection[69].As
attainedbyCOVID‐19clinicaltrials,susceptibilitytoCOVID‐19infectionisinadirect
correlationwiththeactivityofACE2.Sincethisenzymeisenrichedinthelungs,heart,
brain,kidneys,intestine,testes,andplacenta[70–72],thereisahigherrateofviruspres‐
enceandpathogenesis[73].TheseresultsindicatedthatAgIIislikelytobetheprimary
targetofSARS‐CoV‐2inthelungs[68].Moreover,therearesexdifferencesintheexpres‐
sionofACE2.SexhormonesinmalesmadeahigherexpressionofACE2thaninfemales,
withagreaterinfectiousrate[68,74].TheACE/ACE2activityratioinmaleserumishigher
thaninfemales.Individualswithcoexistingdisorders,includingpneumonia[73],diabe‐
tes[75],alongwithaging[74,76,77],cigaretteuse[78],pregnancy[71,79],hypoxia,and
HIF‐1α[62,80],wereshowntobemoresusceptibletothedysregulationoftheACE/ACE2
ratio.Overall,themolecularmechanismsandsignalingpathwaysbywhichSARS‐CoV‐2
elicitsitsharmfuleffectsareincompletelyunderstood,andafewmoleculeshavebeen
identifiedasatargetofSARS‐CoV‐2.Forinstance,ithasbeenshownthatSARS‐CoV‐2
reinforceschemokine‐associatedinflammationandfibrosisthroughIFN,withACE2‐in‐
ducedRas/Raf/mitogen‐activatedproteinkinasekinase(MEK)/ERK/activatingprotein1
(AP1)andcaseinkinase(CK)2‐p21‐activatedkinase1(PAK1)signalingpathways[81].It
hasbeenreportedthattheaforementionedpathwayoffersthepotentialforpulmonary
vascularremodelingandexaggeratedhypoxia[82].AberrantactivationofPAK1hinders
immunesystemsandparticipatesinthepromotionofviralinfection[83].Therefore,the
suppressionofPAK1oritisupstreampotentiallyrepressedSARS‐CoV‐2infection.In
casesofSARS‐CoV‐2infection,ACE2hasattractedsubstantialattentioninCOVID‐19
pathogenicity[69].InappropriateregulationofACE2/Ag(1–7)/Masreceptorand
ACE1/AgIItype1receptorpathwayscouldenhanceACE2,andtherebyincreasethe
chancesofviralentry[69,84].Ontheotherhand,downregulationofACE2bySARS‐CoV‐
2infectioninhibitsthedegradationofAgIIintoAg(1–7),exacerbatesinflammation,and
leadstovascularpermeabilityandcardiovascularcomplications[69].
4.2.TMPRSS2
Ithasbeenwell‐establishedthattheproteolyticcleavageoftheviralenvelopeglyco‐
proteinbyeitherintracellularorextracellularproteases,suchastrypsin,furin,cathepsin,
ortransmembraneproteaseserine2(TMPRSS2),playsanimportantroleinSARS‐CoV
entry[85].Amongthem,TMPRSS2hasbeenshowntoactivatethespike‐proteinof
COVID‐19forviralfusionandinfectivity[86].Anaccumulationoffindingshighlighted
thatthehostproteaseTMPRSS2,employedfortheentryofSARS‐CoV‐2intolungepithe‐
lium,isanattractivetargetforpharmacologicintervention.Ithasbeenshownthatphar‐
macologicinhibitionofTMPRSS2blocksSARS‐CoV‐2entryintohumanlungcells.Addi‐
tionally,inhibitionofTMPRSS2preventedSARS‐CoV‐1infectioninanimalmodels.The
TMPRSS2geneexpressesaproteinof492aminoacidswhichanchorstotheplasmamem‐
brane.Itcanbedividedintothecatalyticchainandnoncatalyticchainpartsthroughau‐
tocatalyticcleavagebetweenArg255andIle256.Aftercleavage,themajorityofmature
proteasesaremembrane‐bound,buttheirsubstantialportionscanbereleasedintothe
extracellularspace[87].IthasbeenrevealedthatTMPRSS2genepromoterpossesses15‐
bpandrogenresponseelement,andTMPRSS2transcriptionisupregulatedinthepresence
ofandrogens[88].TheactivationofSARS‐CoVbyTMPRSS2suppressestheblockageof
SARS‐CoVbyIFN‐inducedtransmembraneproteins,aclassofIFN‐stimulatedhostcell
proteinsthatparticipateininhibitingtheentryofvariousenvelopedviruses[89].

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TMPRSS2isknownasakeygeneinprostatecancer[90].Thehepatocytegrowthfac‐
tor(HGF)/c‐MetcellisactivatedbyTMPRSS2,provokingthesurvivalpathwayofHGF/c‐
Metreceptortyrosinekinasesignalingandstimulatingapro‐invasiveroleinprostatecan‐
cercells.TMPRSS2alsoinducesinflammationbyproteolyticallyactivatingtheprotease‐
activatedreceptor‐2(PAR‐2)intheprostate.Additionally,theupregulationofPAR‐2pro‐
motesmatrixmetalloproteinase‐2(MMP‐2)andMMP‐9,bothofwhichplayakeyrolein
themetastasisoftumorcells[89,91].
4.3.Glucose‐RegulatedProtein78(GRP78)
Glucose‐regulatedprotein78(GRP78),whichbelongstotheheatshockprotein70
family,isthemasterchaperoneproteinpresentinthelumenoftheER[92,93].Undercell
stress,overexpressedGRP78canescapeERretentionandtranslocatetothecellmembrane
[94].Oncelocalizedintheplasmamembrane,GRP78issusceptibletovirusrecognition,
therebyfacilitatingtheviralentrytothehostcells.IthasbeenreportedthatGRP78isa
targetreceptoroftheMERS‐CoVspikeproteinandbatcoronavirusHKU9(bCoV‐HKU9)
[95].Recently,theexistenceofaSARS‐CoV‐2spikeprotein‐GRP78bindingsitehasbeen
predictedusingthecomputationalmethod[96],thuspavingtheroutetodesignsuitable
inhibitorstopreventbindingandinfection.
4.4.TheClusterofDifferentiation147(CD147)
Theclusterofdifferentiation147(CD147),alsoknownasextracellularmatrixmetal‐
loproteinaseinducer,hasrecentlyemergedasanimportantreceptorforSARS‐CoV‐2[97].
CD147possessestheabilitytointeractwithvariousextracellularandintracellularpart‐
nerswhichplayakeyroleintheinfectionprocessofthehumanimmunodeficiencyvirus
(HIV),measles,andSARS‐CoV[98,99].IthasbeenreportedthatCD147canbindwith
multipleligands,includingcyclophilins,monocarboxylatetransporters,caveolin‐1,and
integrins[100].Asextracellularinteractivepartners,cyclophilinsAandBcanbindto
CD147andactivateit,therebyincreasingthechanceofinfectionofCD147‐expressingcells
[101].IthasbeenreportedthatcyclophilinsAandBcaninteractwithnsp1ofSARS‐CoV
[98];however,itisyetnotunderstoodwhethercyclophilinscanbindtoSARS‐CoV‐2.In
aninvitrostudy,Wangetal.[102]revealedthatmeplazumab,ananti‐CD147antibody,
significantlyhinderedtheinvasionofhostcellsbySARS‐CoV‐2.Surprisingly,thisreport
hasbeensupportedbyaclinicaltrialinwhichtheanti‐CD147antibodyinhibitedSARS‐
CoV‐2spikeproteinbindingandsubsequentlyfacilitatedaviralclearance[103].CD147
alsoparticipatedintheregulationofnuclearfactor‐kappaB(NF‐κB).Moreover,upregu‐
lationofCD147leadstotheactivationofNF‐κBwhich,inturn,involvesinflammation
andproliferativeresponses[104].Additionally,cyclophilin–CD147interactioncanrecruit
theimmunecellstothesitesofinflammationviachemokine‐likeactivity[105].Cyclo‐
philin60isidentifiedasanimportantcontributorproteinintheexpressionandtranslo‐
cationofCD147tothecellsurface[106].SeveralotherproteinswhichbindtoCD147may
affectitslocalization.Forinstance,theinteractionofCD147withtheproton‐coupled
transportersofmonocarboxylate,includingMCT1andMCT4inthecellmembrane,is
highlydependentonglutamicacidresidue218intheCD147transmembranedomain.
However,themutationofthisglutamicacidpreventstheaccessofbothCD147andMCT
tothecellmembrane[107].Ithasbeenalsoreportedthatcaveolin‐1bindstoCD147ona
cellsurface,throughwhichitplaysakeyroleintheregulationofclusteringandactivity
ofCD147[108].AsaninteractingpartnerofCD147,integrinβ1interactswithCD147to
regulateintegrin‐dependentsignalingandfocaladhesionkinase(FAK)activation,lead‐
ingtoignitionofthedownstreamsignalingRac/Ras/Raf/ERKandphosphoinositide3‐
kinases(PI3K)/Aktpathwaysandanincreaseinthemetastaticpotentialofhepatocellular
carcinoma[109].IthasbeendemonstratedthatCD147increasesMMPsexpression
throughseveralsignalingpathways,includingJanuskinase(JAK)/signaltransducerand
activatoroftranscription(STAT),Ras‐MEK1‐MAPK,andPI3K/Aktsignalingpathway
[110].

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4.5.DipeptidylPeptidase(DPP4)
Dipeptidylpeptidase(DPP4),alsoknownasCD26,wasconsideredasthemainentry
receptorforMERS‐CoV[111].TheSproteinofMERS‐CoVspecificallyinteractswithDPP4
receptors,therebyinducingproteolyticactivationofviralentranceandviralmembrane
fusionwiththecellmembrane[112].Thereisaboutan80%genomesequencesimilarity
betweenMERS‐CoVandSARS‐CoVwithSARS‐CoV‐2.Recentevidencehasshownthat
DPP4/CD26canalsobindtotheS1domainoftheSARS‐CoV‐2spikeglycoprotein,indi‐
catingthepotentialroleofDPP4/CD26inSARS‐CoV‐2adhesion/virulence[113].Thepo‐
tentialinteractionbetweenSARS‐CoV‐2spikeglycoproteinsandDPP4hasbeendemon‐
stratedbydockingstudiesandneedsin‐depthclarificationinexperimentalmodels[114].
Intriguingly,thereisalsoevidencesuggestingthatDPP4isimplicatedintheinductionof
cytokinestorm,oxidativestress,theimmunesystem,andapoptosis[115].DPP4hasbeen
widelystudiedbecauseofitsproteolyticactivityonvariouscytokinesandpeptidesthat
participateindifferentmedicalconditions[116].Inthecaseofproteolyticactivity,DPP4
reducesincretinssuchasglucagon‐likepeptide1(GLP‐1)andglucose‐dependentinsu‐
linotropicpolypeptide(GIP),subsequentlyleadingtoadeclinedinsulinsecretionandab‐
normalglucoselevel[116].Additionally,DPP4proteolysisleadstopartialortotalaltera‐
tioninsignalingandfunctionalityofitssubstrates,includingpeptidetyrosine‐tyrosine
(PYY),neuropeptideY(NPY),andstromal‐derivedfactor1(e.g.,SDF‐1andCXCL12)
[117].Intriguingly,thereisalsoevidencesuggestingthatDPP4isimplicatedintheinduc‐
tionofcytokinestorm,activationofNF‐κBpathway,oxidativestress,theimmunesystem,
andapoptosis[115].IthasbeenrevealedthatCD26/DPP4possessestheabilitytodirectly
triggerTcellactivationthroughCARMA1‐mediatedNF‐κBactivationinTcellswhich,in
turn,leadstoTcellproliferationandpro‐inflammatoryinterleukin(IL)‐2cytokinepro‐
duction[118].Peoplewithdiabetesareathigherriskofdevelopingtheseriousclinical
eventscausedbyCOVID‐19becausechronichyperglycemiaandinflammationcontribute
toanineffectiveimmuneresponse[119].Inthisline,DPP4inhibitorsand/orGLP‐1recep‐
toranalogsarewidelyusedforthecontrolofhyperglycemiaintype2diabetes[120].The
potentialroleofDPP4inhibitorsinCOVID‐19‐infectedpatientswithtype2diabetesis
notcompletelyclarified.However,DPP4mayillustrateapotentialtargetfordecreasing
theprogressionofthecomplicationsoftype2diabetesinthoseinfectedwithCOVID‐19
[119].Therefore,DPP4inhibitionmayhindertheinfectionand/ordevelopmentofthe
COVID‐19.
5.COVID‐19:Pathogenesis,DysregulatedPathwaysandBeyond
PatientsinfectedwithSARS‐CoV‐2exhibitedvariousclinicalmanifestationssuchas
fever,dyspnea,myalgia,andviralpneumonia[121].Incomplicatedpatients,ARDS,acute
kidneyinjury,cardiovascularcomplications,neurologicalsideeffects,andmultipleorgan
failurehavealsobeenshowntobeassociatedwithincreasedmortality[49,122,123].While
thepathobiologyofSARS‐CoV‐2andmolecularmechanismsbehindtheaforementioned
clinicalmanifestationsarenotyetentirelyknown,therolesofinflammation,oxidative
stress,apoptosis,andautophagyareundeniable.
5.1.RoleofInflammationinCOVID‐19
Aspreviouslymentioned,inflammatorypathwaysplayimportantrolesinthehighly
inflammatoryconditionsofpathogenesisinCOVID‐19[124].Assuch,inseverecasesof
COVID‐19,patientsshowedhigherserumlevelsofinflammatorycytokines,including
TNF‐α,IL‐2,IL‐6,IL‐7,IL‐10,IFN‐γ,IL‐1β,IL‐12,IL‐18,IL‐33,tumorgrowthfactor‐β
(TGF‐β),macrophageinflammatoryprotein‐1α(MIP‐1α),monocytechemoattractantpro‐
tein‐1(MCP‐1),granulocyte‐colonystimulatingfactor(G‐CSF),interferon‐induciblepro‐
tein‐10(IP‐10),chemokines(e.g.,CXCL8,CXCL9,CXCL10,CCL2,CCL3,CCL5)[13,125–
128],andc‐reactiveprotein(CRP)[129–131]intheearlyphaseasmajorcausesofARDS

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[132].Extensiveimmunologicalresponses,highlevelsofcirculatinginflammatorycyto‐
kines,substantiallymphopenia,andimmune‐cellinfiltrationarecloselycorrelatedtoim‐
mune‐pathologicalchangesoftargetedorgans[133].
InCOVID‐19patients,increasedneutrophils/CRPanddecreasedlymphocyteswere
revealed;thiswasindirectcorrelationwithdiseaseseverity[13].Releasingtheaforemen‐
tionedinflammatoryfactorsisalsocalledacytokinestorm,which,inturn,leadstovarious
pathogeniccomplicationsinCOVID‐19[134–136].Theinnateimmunesystemalsoem‐
ploysIFNtypeI,IFN‐αandIFN‐β,andIFN‐stimulatedresponseelement(ISRE)asdown‐
streammediatorsinexertingacriticalresponseagainstviralinfection,whileareduced
IFNleadstorapidviralreplication[137,138].Consequently,IFN‐α/βsuppressesviraldis‐
semination/replicationintheearlystageofviralinfection.COVID‐19employsmultiple
waystowardinterferingwiththeaforementionedpathwaysoftypeIIFNproduction
[127,139],includingJAK‐STAT/ISREpathwayphosphorylation[140].Followingthepro‐
ductionoftypeIIFN,COVID‐19isequippedtosuppresstheinflammatorypathways
[65,140,141],time‐dependently[127].Additionally,anydysregulationinthepathway
leadstoneutrophil/monocyte/macrophageactivationandlethalpneumoniaoracuteres‐
piratorydistresssyndrome[127].AdisturbanceintheregulationofIFNsgenerationof
pro‐inflammatorycytokinesproducedbymacrophagescontributestotheapoptosisofT
cells,whichfurtherhampersviralelimination[142].Duringviralinfectionandactivation
oftheadaptiveimmuneresponse,theengagementoftheTcellreceptorprovokesintra‐
cellularcalciumoverloadwhich,inturn,inducescalmodulinbindingtocalcineurin.Cal‐
cineurinactivationparticipatesinthenuclearfactorofactivatedT‐cell(NFAT)
dephosphorylation[143].Thecalcium‐calcineurin‐NFATpathwaybooststhegeneration
ofpro‐inflammatorycytokines,therebymaintainingchronicinflammationconditions
[144].
Asotherinvolvedreceptors,TLR‐7andTLR‐3activatethedownstreamsignaling
cascade,includingNF‐κBandIFNregulatoryfactor3(IRF3)[140].Enhancedlevelsofpro‐
inflammatorycytokinesandthemigrationofinflammatorycellsintothelungtissuesare
thepostulatedmechanismsforacutelunginjury.Cytokinestormdisruptstissueintegrity
andsubsequentlyleadstopneumonitis[145].Activationofvariousinflammatorycyto‐
kinesinvolvedinthecytokinestormiscontrolledbytheintracellularsignalingpathway
JAK/STAT[146].Forinstance,IL‐6whichhasbeenprovenasapivotalinflammatorycy‐
tokine,employstheJAK/STATpathwaytoperformitsbiologicalfunctionssuchasim‐
muneresponse,inflammation,andoxidativestress.TheinhibitionoftheIL‐6/JAK/STAT
pathwayappearsapromisingtherapeuticoptionforthealleviationofCOVID‐19[147].
5.2.RoleofOxidativeStressinCOVID‐19
Oxidativestressisconsideredakeycontributortotheseverityandpathogenesisof
SARS‐CoV‐2.Over‐generationofreactiveoxygenspecies(ROS)andantioxidantdepletion
driveapivotalroleinviralreplicationandviral‐relatedcomplications[148,149].Some
populationsofinnateimmunecells,suchasmacrophagesandneutrophils,wouldgener‐
ateROStoclearthepathogens[150,151].DespitethenecessityofROSproductionbymac‐
rophagesandmonocytesformodulatingimmuneresponsesandeliminatingviralinfec‐
tion,relatedover‐productioncontributestotheoxidationofcellularproteins/lipidsand
corruptsbothinfectedandnormalcells,therebyleadingtomultipleorgandysfunctions
[152].Moreover,compellingstudieshaveshownthatviralinfectionssuchaSARS‐CoV
arelinkedtotheinhibitionofNrf2andaugmentationofNF‐κBsignaling,leadingtoanti‐
oxidantdeprivationandinflammation[153].Nrf2,anditsdownstreamtargetantioxidant
enzymehemeoxygenase‐1(HO‐1),servesasacrucialsignalingpathwayforcytoprotec‐
tionagainstinflammationthroughinhibitingcriticalinflammatoryregulatorypathways
suchasNF‐κB[148].Interestingly,Nrf2‐keap1/HO‐1activationaccompaniedbyanin‐
creaseinenzymatic/non‐ enzymaticantioxidantactivities,includingsuperoxidedis‐
mutase(SOD),catalase(CAT),glutathioneperoxidase(GPx),glutathione(GSH),thiobar‐
bituricacidreductase(TBARS),NAD(P)H:quinoneoxidoreductase1(NQO‐1),which,in

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turn,suppressoxidativemediatorsandlipidperoxidation,therebyalleviatingthehall‐
marksofviralinfection[154,155].Therefore,theNrf2pathwayisanauspicioustherapeu‐
tictargetforcombatingSARS‐CoVpathogenesis.
5.3.RoleofApoptosisinCOVID‐19
ApoptosisisadeterminerpathwayinvolvedinCOVID‐19complications.Asapath‐
ogenicpathway,apoptosisinductionininfectedcellscandirectlyleadtoviralpathogen‐
esis[156].InSARS‐CoV‐infectedpatients,lymphopeniamayoccurduetoTcelldiminu‐
tionthroughtheactivationofapoptosis[157].Apoptosisactivationmediatedbyhuman
COVID‐19infectioncontributestothespreadofthevirus[158].Apoptosisactivationis
associatedwithnumerousabnormalitiesinvirallyinfectedorgans.Inthisline,SARS‐
CoV‐2infectionstimulatedapoptosisinlungepithelial/endothelialcells,whichcauses
vascularleakageandalveolaredema,aswellasacutelunginjury[29].Severalmecha‐
nismsareinvolvedinapoptosisactivationbyhumanCOVID‐19.Ithasbeenreportedthat
humanCOVID‐19stimulatesapoptosisviaER,caspase‐mediated,p38MAPK,andc‐Jun
N‐terminalkinase(JNK)dependentpathways,whichareneededforviralreplication
[159,160].Fromanotherpointofview,SARS‐CoVtriggersapoptosisthroughdecreasing
anti‐apoptoticB‐celllymphoma2(Bcl)‐2members(e.g.,Bcl‐2andBcl‐xL)andkeysurvival
signalingpathwayssuchasAkt.TheupregulationofAktinactivatedseveralpro‐apop‐
toticmoleculessuchasglycogensynthasekinase‐3β(GSK‐3β),caspase‐9,Bad,andfork‐
headtranscriptionfactorFoxo1(FKHR),therebyhamperingapoptoticpathways[161].
Virusinfectioncantriggerpoly (ADPribose)polymerase(PARP)andultimatelyresultin
apoptosis.PARPdrivesanimportantroleinprogrammedcelldeathandcytokinerelease
[162,163].Therefore,PARPinhibitorscanbeservedassupportivetreatmentsforalleviat‐
ingthehallmarksofCOVID‐19.Besides,viralinfectionsdisruptmitochondrialmembrane
potentialandprovokepro‐apoptoticfactorssuchascytochromeC,caspase‐9,and
caspase‐3[164,165].Therefore,targetingparticularmediatorsandenzymesoftheapop‐
toticpathwayisanattractivestrategyforfightingaviralinfection.
5.4.RoleofAutophagyinCOVID‐19
AsanothercriticalpathwayforCOVID‐19,autophagyisanintracellularregulated
processthatplaysapivotalroleinthemaintenanceofcellularhomeostasis[166].Consid‐
eringmechanisticchangesinCOVID‐19,autophagyisafundamentalcellprocessinthe
pathogenicityofdisease.Thisprocessischaracterizedbytheformationofthedouble‐
membraneautophagosomesthatsubsequentlyfusewithacidiclysosomestoformautoly‐
sosomesthroughapH‐dependentmechanism.Theengulfedcomponentsarethende‐
gradedwithlysosomalenzymes[167].Thereisincreasingevidencethatdysregulatedau‐
tophagyseemstoplayanessentialroleinthepathogenesisofSARS‐CoV,aswellasits
arisingcomplications.Alteredautophagycausedbyviralinfectionisstronglyassociated
withseveretissuedamage.Ontheotherhand,autophagycouldbeconsideredadouble‐
edgedswordinthepathogenesisofSARS‐CoV.Thepro‐viralorantiviralroleofautoph‐
agyremainsunclear[149].Thevirusthatentersthehostcellcaneitherbeeliminatedvia
autophagyorescapeautophagicdegradationandreplicateinthehostcell[168].Acentral
aspectofthepro‐viralroleofautophagyistoboostviralreplicationbytheformationof
double‐membranevesiclesinthehostcells.Infact,virusreplicationinthehostcellbegins
attheER‐Golgiintermediatecompartment,whichisconnectedtoautophagosomebio‐
genesis,wheretheviralgenomepossessesacriticalinteractionwiththeproteinsthatare
necessarytoassembleacompletevirus[169,170].Ithasbeenidentifiedthatviralnsp6
proteinwasfoundtoco‐localizewiththeendogenousautophagymarker,LC3,suggesting
apossiblecollaborationbetweenautophagyandCOVID‐19replication[168].Therapeu‐
ticssuchaschloroquineandhydroxychloroquineelicitantiviraleffectsbyinhibitingthe
fusionofautophagosomesandlysosomes,andblocksthelaterstagesofautophagicflux
[171].Ontheotherhand,theinductionofautophagymaycombatviralinfectionbythe
degradationofviralcomponentsandtheaugmentationofinnateandadaptiveimmunity

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[172].Inductionofautophagyandinflammatoryresponsesinducedbyviralinfectioncon‐
tributetolunginjury[173].IthasbeenreportedthattheinhibitionofS‐phasekinase‐as‐
sociatedprotein2(SKP2),whichisresponsibleforproteasomaldegradationofBeclin1,
enhancedautophagy,andsubsequentlyattenuatedthereplicationofMERS‐CoV[174].A
novelanalysishasalsohighlightedtherelationbetweenautophagymechanismsandan‐
tiviral/inflammatoryresponsesinCOVID‐19.Inthissense,PI3K/Akt/mammaliantarget
ofrapamycin(mTOR)isakeycontrolsignalingpathwayforautophagythatregulates
variousautophagymediators,suchasBeclin,microtuble‐associatedproteinlightchain3
(LC3),andautophagy‐related(Atg).HumanCOVID‐19‐infectedhepatocytescouldin‐
duceautophagythroughERK/MAPKandinhibitionofthePI3K/Akt/mTORpathway
[175].Additionally,JNK,AMP‐activatedproteinkinase(AMPK),p38MAPKcontrolthe
balanceoftheautophagyresponsetoviralinfection[176–178].Consideringtheroleofthe
aforementionedmediatorsinautophagy,modulatingautophagicpathwayscouldpave
theroadforcombatingSARS‐CoV‐2infection[170].
Overall,theinhibitionofautophagyduringthefirstphaseofCOVID‐19couldpre‐
ventthereplicationofSARS‐CoV‐2andnegativelyregulatetheIFNresponse.Onthe
otherhand,autophagicpathwaysareinanearlinktoinflammationandimmunere‐
sponsesinCOVID‐19.Accordingly,dysregulationinautophagicpathwayscouldleadto
cytokinestormandimmunedysfunction.Consequently,autophagymodulationrestores
homeostasisintheimmuneresponseofCOVID‐19torepresentanimportantchallenge,
indicatingtheabilitytoimproveantiviralresponse,restrictinflammation,andprevent
othercomplications[179].Therefore,amechanistictargetingofautophagyshouldbecon‐
sideredanewstrategyincombatingSARS‐CoV‐2.
6.TherapeuticInterventionsforCOVID‐19
ShortlyaftertheidentificationofCOVID‐19inChina,manystudiesdemonstrated
theeffectivenessandadvantagesofdifferentclassesofdrugswhenhopingtofindasuit‐
ableagentwithpromisingeffectsintheprevention,control,recovery,andimprovement
ofrelatedpathologicalconditions.Ithasbeenwell‐establishedthatinflammation,apop‐
tosis,oxidativestress,autophagy,andhostfactors,aswellasdestructivesignalingpath‐
ways,playacrucialroleinthepathogenesisofSARS‐CoV‐2.Therefore,modulationofthe
dysregulatedtherapeutictargetsandpathwaysisanattractivetherapeuticavenuefor
COVID‐19.
6.1.TargetingAutophagyandApoptosis
Prevailingevidencehashighlightedthecross‐talkandthebalancedinterplaybe‐
tweenautophagyandapoptosis[180].Theover‐accumulationofautophagosomepro‐
motestheapoptoticpathwaythateventuallycausesapoptoticdeathofthevirallyinfected
cellsandrepressesthevirusreplicationcycle[181].Therefore,providingalternativether‐
apiesthatpotentiallyinterferewithSARS‐CoV‐2andleadtoautophagyregulationisof
greatimportance.Todate,therearenoproveneffectivetherapiestopreventorcure
COVID‐19.Anaccumulationoffindingssuggeststhatseveraldrugsunderclinicaltrials
forSARS‐COV‐2areautophagy/apoptosismodulators.Forinstance,chloroquine/hy‐
droxychloroquine,emtricitabine/tenofovir,IFN‐α‐2b,lopinavir/ritonavir,andruxolitinib
contributetoautophagosomeaccumulationthroughinhibitingautolysosomeformation
andtherebydisruptthereplicationofSARS‐CoV‐2[182].Additionally,corticosteroids
suppressautophagybyinhibitingLC3recruitment[183].Besides,ruxolitinib,asaJAK
inhibitorcaninduceautophagythroughblockingmTORC[184].
Altogether,modulatingapoptosisandautophagyseemstobeahopefulstrategyin
combatingCOVID‐19.
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6.2.TargetingOxidativeStress
Viralinfectionsprovokecytokinestorm,whichinturnleadstooxidativedamage.
Therefore,alleviationandmanagementofoxidativedamagescanbeachievedbyalarge
doseofantioxidants[185].VitaminCpossesseswell‐characterizedantioxidantproperties,
beingabletoscavengefreeradicalsandtherebypreventcellsandtissuesfromoxidative
damage[186].Apartfromitsantioxidantproperty,evidenceisaccumulatingthatvitamin
CexhibitsantiviralactivitybyaugmentingIFN‐αproduction,decreasinginflammation,
amelioratingendothelialdysfunction,andalsodirectvirucidalactivity[187].Arandom‐
izedplacebo‐controlledtrialrevealedthatthehighdoseofintravenousvitaminCcanim‐
provepulmonaryfunctionanddecreasetheriskofARDSin308patientsdiagnosedwith
COVID‐19andtransferredintotheintensivecareunit[188].VitaminEisakeylipophilic
antioxidantthatmitigateslipidperoxidation[189].Thisvitaminalsoregulatesimmune
responseandstabilizesmembranecells.TheimportanteffectsofvitaminEmakeitapo‐
tentialcandidateforthealleviationofoxidativedamageandinflammationinducedby
SARS‐COV‐2[190].Moreimportantly,astaxanthin,alipid‐solublecarotenoidthatpos‐
sessesahigherantioxidanteffectthanvitaminEandvitaminC,canbeconsideredasa
potentialoptionincounteractingCOVID‐19complications[191].
6.3.TargetingSARS‐CoV‐2Invasion
TargetingthelifecyclestepsofSARS‐CoV‐2,includingvirusattachmentandendo‐
cytosis,viralreplication,andtranscription,aswellasvirusassemblyandrelease,provides
apromisingtherapeuticapproach.Theauspiciousdrugtargetsencompasshostfactors
(e.g.,ACE2,TMPRSS2,andCD147),andNSPs(e.g.,RNA‐dependentRNApolymerase,
and3‐chymotrypsin‐likeprotease),alongwithstructuralproteins.Interestingly,serine
proteaseinhibitors,suchascamostat,wereidentifiedassuppressingTMPRSS2andeffec‐
tivelydecreasingmortalityfollowingSARS‐CoVinfection[11].Moreimportantly,Hoff‐
mannetal.revealedthatthisdrugpossessestheabilitytoabrogateSARS‐CoV‐2entry
intolungcellsbysuppressingACE2andTMPRSS2[192].Basedonpreclinicalinvestiga‐
tions,adouble‐blindrandomizedcontrolledclinicalstudywasperformedwith114
COVID‐19infectedpatientstofindwhethercamostatmesylateatadoseof200mg/3times
adaycandiminishaSARS‐COV‐2viralloadinearlyCOVID‐19disease(NCT04353284).
Inanopen‐labelphase2clinicaltrial,meplazumab,ananti‐CD147antibody,inhibited
SARS‐CoV‐2spikeproteinbindingandcouldblocktheinfectionofSARS‐CoV‐2in20
COVID‐19patientswithpneumonia[103].
Ithasbeenreportedthatarbidolpossessesanattractivemechanismofactionthat
affectstheSprotein/ACE2interaction,haltingviralmembranefusion[193].Anon‐ran‐
domizedstudyrevealedthattreatmentwitharbidolforninedaysdecreasedmortality
ratesandenhanceddischargeratesin67patientsinfectedwithCOVID‐19[194].Asanti‐
viralchances,combinedlopinavir/ritonavircombinationas3‐chymotrypsin‐likeprotease
inhibitorsofanti‐retroviraldrugswassuggestedasaneffectivedrugagainstMERS‐CoV
andSARS‐CoV[195,196].Forthisreason,severalclinicaltrialshavebeenperformedto
investigateitseffectsonCOVID‐19.Theresultsofthosestudieswerenotsufficientand
didnotrecommendcombinationtherapyasasuitablemedication[1,197].Theadvantages
ofnewstudiesemphasizedthatarbidolmonotherapywasmoreimpressivethanlop‐
inavir/ritonavirinthetreatmentofpatientswithCOVID‐19.About14daysafterthetreat‐
ment,viralloadwasnotidentifiedinthearbidolgroup,andthedurationofthepositive
RNAtestwasshorterinthisgroup[198].
Favipiravirisabroad‐spectrumRNApolymeraseinhibitor,anantiviralcompound
thatshowedasuitableactivityversustheCrimean‐Congohemorrhagicfever,rabies,osel‐
tamivir‐resistant,andwild‐typeinfluenzaBvirusinmice[199–201].Forthisreason,an
open‐labelcontrolstudywasperformedtoinvestigatetheadvantagesoffavipiraviron
COVID‐19,andresultsshowedimprovementinthechestimagingincomparisonwiththe
controlgroupandmightbeausefulagentinthetreatmentofCOVID‐19[202].Moreover,

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remdesivirisanewnucleotideanalogandRNA‐dependentpolymeraseinhibitorthat
showedconsiderableinvitroactivityversusSARS‐CoV‐2[203].Anemergencyuseau‐
thorizationforremdesivirwasissuedtoadultsandchildrenhospitalizedwithCOVID‐19.
Wangetal.designedadouble‐blind,randomizedtrialtoinvestigatetheeffectof
remdesivirin237patientswithsevereCOVID‐19.Comparedwithplacebo,remdesivir
couldnotsignificantlyreducethedurationofhospitalizedtimeinpatientswithCOVID‐
19[204].Besides,anotherRNA‐dependentpolymeraseinhibitor,ribavirin,whichisrou‐
tinelyusedincombinationwithIFNforhepatitisCvirusinfection,couldnotfindenough
evidencetotreatCOVID‐19[205].Darunavirisaproteaseinhibitorthathasshownbene‐
ficialeffectsintreatingHIV‐1infection.InFebruary2020,aclinicaltrialwasregisteredin
Chinatoperusetheadvantagesofthisdrugincombinationwithcobicistat,ahumancy‐
tochromeP‐4503Aenzymeinhibitor;thusfar,nodatasupporttheefficacyandsafetyof
thisagentinhumansdiagnosedwithCOVID‐19(NCT04252274).
Thereisinadequateandinsufficientinformationthusfartoknowwhetherchloro‐
quineorhydroxychloroquinehasaremarkableroleinthetreatmentofCOVID‐19.Both
hydroxychloroquineandchloroquinehavebeendocumentedtoinhibitSARS‐CoV‐2in
vitro;however,itseemsthattheantiviralpotentialofhydroxychloroquineismorethan
chloroquine.Theantiviralmechanismsofhydroxychloroquineandchloroquinearenot
fullyrealized,butinhibitingviralfusion,changingthepHatthecellmembranesurface,
inhibitingandsuppressingthereplicationofnucleicacid,preventingviralassemblyand
release,anddecreasingtheglycosylationofviralproteinsareamongsttheirimportant
possibleantiviralmechanism[203,206].Evenso,theobtainedclinicaldataoneitherofthe
twocompoundsarelimitedandhaveseriousmethodologicalproblems.Inanopen‐label
studyperformedinMarch2020,theadministrationof200mghydroxychloroquinethree
timesperdayfortendaysincreasedtherateofundetectableSARS‐CoV‐2RNAinsamples
obtainedfromnasopharyngealincomparisonwiththeplacebogroup[207].Significant
methodologicproblemsreducedthevalueofthosestudiesandmadetheresultsunrelia‐
ble[208].Anotherrandomizedtrialwithastatisticalpopulationof30adultswithCOVID‐
19wasperformedinShanghai.Theresultsofthosestudiesdidnotshowasignificant
differencebetweenthegroupreceivinghydroxychloroquineandthegroupreceiving
standardcare[209].Furthermore,adverseeffectsduetohighdosesofchloroquineand
increasedmortalitypreventedpatientsfromcontinuingthestudies[210].
6.4.TargetingInflammation
Fromaninflammatorypointofview,thecriticalroleofinflammatoryresponsesand
enhancedinflammatorycytokinesinCOVID‐19arethemostcriticalfactors.Inthisregard,
thelevelofIL‐6showedaconsiderablecorrelationwiththeseverityofCOVID‐19,andthe
measureofthiscytokinecanbeusedasanimportantfactorinpredictingdiseaseseverity
[211].TocilizumabisaselectiveantagonistoftheIL‐6receptor,whichpreventedcytokine
releasesyndromeandledtoimprovingtheconditionsofapatientwithsevereCOVID‐19
[212].Severalclinicalstudieshavebeenconductedinvariouscountries,includingthe
UnitedStates,Spain,Nepal,Malaysia,andBelgium,toinvestigatetheeffectsofthisdrug,
butthefullresultsofthesestudieshavenotyetbeenpublished(NCT04332094,
NCT04377659,NCT04331795,NCT04330638,NCT04317092,NCT04345445).Siltuximab
andsarilumabareotherreceptorantagonistsofIL‐6thatareintheearlystagesofclinical
research(NCT04329650,NCT04322188,NCT04341870,NCT04357808).Consistently,it
seemsthattheIFN‐βSubtypemaybeasuitableoptionforCOVID‐19treatment.IFN‐β
properlydecreasedtheMERS‐CoVinvitroandhashadpleasantoutcomesinananimal
modelofMERS‐CoVinfection,butnodataevaluatedtheadvantagesofIFN‐βonSARS‐
CoV‐2[195,213,214].
AstheimportanceofJAK/STATinthepathogenesisofCOVID‐19wasshownprevi‐
ously,baricitinibisaJAKinhibitorthatleadstotheinactivationofSTATsandadecrease
intheserumlevelsofIgG,IgA,IgM,andCRP.Thelimiteddatademonstratedthatthe
administrationofbaricitinibmaymodifycytokine‐releasesyndromeduetoCOVID‐19.

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TheresultssuggestedthisagentasausefuldrugfordamasceningtotheCOVID‐19ther‐
apyregimen[215];forthisreason,severalclinicaltrialsareinprogresstosifttheeffectof
baricitinibinCOVID‐19(NCT04340232,NCT04321993,NCT04362943).
Glucocorticoidsareofthemainclassesofdrugspossessingimmunosuppressive,
anti‐inflammatory,andantiproliferativeactivitiesthroughblockingIL‐1αandβ,NF‐κB,
TNF‐α,AP‐1,andincreasingthesynthesisof,IκB‐α.Theadministrationofglucocorticoids
inpatientswithinfluenzaledtoadelayinviralclearanceandenhancedriskformortality;
thiswassimilarinpatientswithaMERS‐CoVinfection[216,217].Furthermore,thead‐
ministrationofglucocorticoiddrugsonpatientswithCOVID‐19didnotprovideadequate
andacceptableresults[218].Nonsteroidalanti‐inflammatorydrugs(NSAIDs)havefora
longtimebeenconsideredeffectivetherapiesagainstinflammatorydiseases[219].Tode‐
terminetheefficacyofibuprofen,acommonlyprescribedNSAID,inCOVID‐19,aran‐
domizedphase4clinicalstudywasappliedin230severeCOVID‐19patientstotreatthem
withibuprofenatadailydoseof200mg(NCT04334629).Additionally,arandomized
phase3clinicaltrialwasregisteredtoassesstheeffectivenessofnaproxen(250mgtwice
aday)inpatients(n=584)infectedwithSARS‐CoV2(NCT04325633)[220].Pre‐clinical
evidencehaspreviouslybeenpresentedontheuseofNSAIDsduringCOVID‐19[221].
6.5.MiscellaneousAgents
Inadditiontotheaforementionedagents,antibioticsareusedforpossibleeffective‐
nessincombatingCOVID‐19.Azithromycinisamacrolideantibioticwithconflictingin‐
formationaboutitsconcomitantusewithhydroxychloroquineforCOVID‐19treatment.
However,astudyconductedinMay2020inFranceshowedthattheuseofazithromycin
incombinationwithhydroxychloroquinebeforethebeginningofCOVID‐19complica‐
tionsmaybesafeandledtoaverylowfatalityrateinpatients[222].Thesignificantpo‐
tentialofbothdrugsforcorrectedQTintervalprolongation,aswellasthepossibilityfor
theexacerbationofthiscomplicationintheirsimultaneoususe,preventstheirconcomi‐
tantadministration,anditisnotrecommended[223,224].Asanotherantibiotic,
teicoplaninwasshowntobeeffectiveagainstformercoronavirusesanddemonstratedan
invitroactivityagainstthenovelcoronavirus,butenoughinformationandconvincing
evidencearenotavailablefromclinicaltrials[225].
Asanotherclassofdrugs,ananti‐parasiticdrug,ivermectin,showedasuitablein
vitroeffectonSARS‐CoV‐2[226].Forthisreason,theauthorsadvisedinvestigatingthe
possiblebenefitsofivermectininhumanswithCOVID‐19,andseveralclinicaltrialsbegan
inthehopeofachievingconvincingresults(NCT04360356,NCT04343092,and
NCT04374279).Fromanotherpointofview,oseltamivir,aneuraminidaseinhibitor,indi‐
catedforprophylaxisandtreatmentofinfluenza,didnotshowanysignificanteffectfor
treatmentorprophylaxisofCOVID‐19[205].FromotherdrugsusedagainstCOVID‐19,
theBacillusCalmette–Guérin(BCG)vaccinecouldbementionedforitsuseintheimmun‐
izationagainsttuberculosisandthepreventionofleprosy.TheBCGvaccineshowedin
vitroandinvivonon‐specificprotectiveactivitiesversusotherrespiratorytractinfections.
StatisticalanalysiswasconductedtoinvestigatetheeffectsofvaccineBCGincountries
withandwithoutnationalvaccinationprogramsinpreventingandreducingCOVID‐19’s
mortality.Theresultsshowedthat,incountrieswithvaccinationprograms,thepreva‐
lenceandmortalityratewasestimatedat38.4and4.28peoplepermillion,respectively.
Thedeathratewas40/millionincountrieswithoutBCGprograms[227].Therefore,itis
hypothesizedthatthevaccinemayreducetheincidenceandseverityofCOVID‐19in
healthcareworkers.Inthisregard,severalclinicaltrialsarebeingconductedtoinvestigate
theseeffects(NCT04348370,NCT04373291,NCT04327206,NCT04350931,NCT04328441).
IncreasingevidencehasshownthatvitaminDdeficiencyiscorrelatedwithCOVID‐19‐
associatedcoagulopathy,inflammation,immuneresponsedysfunction,andmortality
[228].Fromamechanisticangle,vitaminDdisplaysantiviralactivitythroughimmuno‐

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modulationandinductionofautophagy[229].IthasbeenreportedthatvitaminDsup‐
plementationmitigatesliverdiseaseprogressionandaugmentsresponsestotherapyin
hepatitisCviruspatients[230].
Othermiscellaneouscompounds,antioxidation,immune‐modulatory,andanti‐in‐
flammatoryactivityofmelatonin,asaneurohormone,madethiscompoundoneofthe
drugswiththepotentialtobeaddedtothetherapeuticregimenofpatientswithCOVID‐
19[231].Thereissomeotherinformationontheprotectiveeffectsofmelatonininviral
diseases,whichmaydisplaytheseadvantagesinpatientswithCOVID‐19[231].
7.ImportanceofPhytochemicalsinCombatingCOVID‐19
Phytochemicalsareaconsequentialsourceofactivechemicalsconstructedbyplants,
withpotentialeffectsagainstpathogens.Theyhavebeenintroducedasinfluentialre‐
sourcesfordrugdiscovery,possessingvarioushumanhealthbenefits.Besides,asubstan‐
tialspectrumofbiologicalactivitiesisreportedforphytochemicals,suchasanticancer,
antibacterial,neuroprotective,cardioprotective,immune‐modulatory,anti‐inflammatory,
andantioxidanteffects[232,233].Severalstepsinviralreplicationandinfectioncanbe
alsosuppressedbynaturalproducts[50].Althoughmanyofthesecompoundshavebeen
showntohavebroad‐spectrumantiviraleffects,themechanismsbehindtheseeffectshave
notyetbeenfullyelucidated.Besidestheirpotentantioxidantactivities,inhibitingthe
synthesisofDNAandRNA,suitablescavengingcapacities,preventionofthevirusentry,
orreproductionofthevirusaresomeofthecriticalreportedantiviralmechanismsofthese
compounds[234].Theimmune‐modulatoryeffectofnaturalproductsandthesignificant
potentialforsuppressingtheinflammatoryreaction,asoneofthemajorreasonsformor‐
talityandmorbidityofSARS‐CoV‐2infection,areotherpromisingmechanismsofphyto‐
chemicalsinthetreatmentofSARS‐CoV‐2[235].Wehavepreviouslyreportedthemodu‐
latoryrolesofnaturalproductsoninflammatory,apoptotic,andoxidativestresspath‐
waysinvolvedinthepathogenesisofCOVID‐19‐associatedlunginjury[35,236].Wehave
alsoshownthattheneuronalmanifestationsofCOVID‐19couldbepotentiallytargeted
byphytochemicals[35].Therefore,inthepresentstudy,wehavefocusedontheinflam‐
matory,apoptotic,oxidativestressandautophagicpathways,andviruslifecycle,aswell
asthephytochemicaleffects.Flavonoids,polyphenolics,alkaloids,terpenoids,coumarins,
andcarotenoidsaresomeoftheimportantgroupsofphytochemicalswithantiviral,anti‐
oxidant,andanti‐inflammatoryactivitiestowardsdevelopingasuitabletherapeuticop‐
tionforCOVID‐19[35].
Asagroupofmulti‐targetedagents,flavonoidsandpolyphenolsarealreadyrecog‐
nizedaspotentialtherapeuticagentsforthetreatmentofviralinfections.Numerousstud‐
ieshaveshownthatcurcumin(aphenoliccompound)possessesanti‐inflammatoryand
antioxidantroles,andinterruptstheviralinfectionprocessviaseveralmechanisms,in‐
cludinghinderingvirusentry,replication,andbudding,directlyinterferingwithviral
proteinsandrepressingthegeneexpressionofthevirus[237–240].Fromanotherpointof
view,curcuminreducedthepro‐inflammatorycytokinesandvirus‐inducedcytokine
storm,aswellasalleviatinglunginjury,therebyindicatingpotentialeffectsinthetreat‐
mentofCOVID‐19[237,241].Accordingtocomputationalmethods,curcuminoffersthe
abilitytoinhibitthespikeproteinofSARS‐CoV‐2anddisruptsviralentry[242].Another
insilicoapproachalsorevealedthatcurcuminandcatechinwereusedaspotentialantivi‐
ralpolyphenolsthroughthedualinhibitionofhostcellreceptorstothevirus(mediated
byACE2)andviralproteinentry(S‐protein).Itshouldbementionedthatthebindingaf‐
finityofcatechinwasmorethanthatofcurcumin[243].
Ithasbeenpreviouslydocumentedthatthebioactiveflavonoidbaicaleinblocksin‐
fluenzaAvirusH3N2throughsuppressingautophagymarkers,Atg‐5,Atg‐12,andLC3‐
II[244].BaicaleincouldeffectivelyabrogatethereplicationofSARS‐CoV‐2inVerocells
throughdiminishing3C‐likeproteases(3CLpro)SARS‐CoV‐2[245].Inanotherstudy,bai‐
caleinmitigatedVeroE6celldamageinducedbySARS‐CoV‐2.Additionally,this
nutraceuticalagentalleviatedthelesionsoflungtissueandsuppressedreplicationof

Molecules2021,26,291715of31
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SARS‐CoV‐2inmice.Furthermore,thiscompoundimprovedrespiratoryfunctionandre‐
ducedinflammation,corroboratedbydecreasingthelevelofIL‐1βandTNF‐αinlipopol‐
ysaccharide(LPS)‐inducedacutelunginjuryofmice[246].Dockingevidencerevealed
thatflavonoidsbiochaninAandsilymarinstronglyinteractwiththeactivesiteofSARS‐
CoV‐2spikeglycoproteinandACE2,respectively[247].
FurtherinvitrostudiesshouldbecarriedoutontheseflavonoidsagainstSARS‐CoV‐
2.Asabest‐dockedbioflavonoid,naringinexhibitedahigh‐affinitybindingatthebinding
siteofmainprotease(Mpro)andspikeglycoproteinofSARS‐CoV‐2[248,249].Ithasbeen
recentlyreportedthattwo‐porechannel2(TPC2)isakeyrequirementforSARS‐CoV‐2
entry[250].Surprisingly,naringeninexhibitedthecapacityofpotentantiviralactivity
againstSARS‐CoV‐2andcouldsuccessfullyabrogateTPC2invitro[251].Furtherinvivo
studiesareneededtoconfirmthebeneficialeffectofnaringenin.
Ithasbeenpreviouslydocumentedthatphytoactiveflavonoidtaxifolinameliorated
sepsis‐inducedpulmonarydamageandedemabyinhibitingtheNF‐κBpathway[252].
Accordingtothemoleculardockingapproach,taxifolinwasfoundapotentialinhibitor
againstMproSARS‐CoV‐2[253].AsaneffectivecandidateagainstSARS‐CoV‐2,theflavo‐
noidsilibinindeclinedimmuneresponseandinflammationbyinhibitingSTAT3,thereby
facilitatingeffectsontheearlystageSARS‐CoV‐2infection[254].Acomputationalstudy
proposedthatsilibininhindersthereplicationofSARS‐CoV‐2viaabrogatingRNA‐de‐
pendentRNApolymerase(RdRp)[255].Silibininoffersexcellentopportunitiesforfurther
investigationsinpreclinicalandclinicaltrialsasananti‐SARS‐CoV‐2agent.Ithasbeen
reportedthattheflavonoidluteolincandisrupttheviralfusionandentryprocessandcan
alsomitigateSARS‐CoVinfectionwithEC50valuesof10.6μMinadose‐dependentman‐
ner[256].
ResveratrolisaphenoliccompoundthatappreciablyinhibitedMERS‐CoVinfection
andcouldenhancecellularsurvivalbehindvirusinfection.Itcouldnotablydecreasean
essentialproteinexpressionforMERS‐CoVreplication(nucleocapsidN),anddownregu‐
latedtheinvitroapoptosisinducedthroughMERS‐CoV[257].Ithasbeenalsoshownthat
resveratrolpotentiallysuppressedSARS‐CoV‐2infectioninvitro[258].Emodinisanother
chemicalcompoundthatbelongstotheanthraquinonecategory.Itwasshowntoblock
andsuppresstheSproteinandACE2interaction,leadingtobeneficialeffectsinthetreat‐
mentofSARS‐CoV[259].Hirsutenone,asabioactivediarylheptanoidpolyphenolisolated
fromAlnusjaponica(Thunb.)Steud.(Betulaceae),exertedstrongantiviralactivitythrough
diminishingpapain‐likeprotease(PLpro)ofSARS‐CoV.Ithasbeenreportedthatcatechol
andα,β‐unsaturatedcarbonylmoietyplaycriticalrolesinproteaseblockingactivity[260].
Alkaloidsareanimportantclassofnaturalproductswithantiviralactivities,which
havebeenextensivelystudied[261,262].Moleculardockingevidenceprovedthepromis‐
ingpotentialofsuchalkaloidsintargetingSARS‐CoV‐2RdRp,including10′–hy‐
droxyusambarensine,cryptospirolepine,andstrychnopentamine[263].Thebioactiveal‐
kaloidemetine,asaviralentryinhibitor,haspreviouslybeenshowntoblockMERS‐CoV‐
mediatedinfection[264].Interestingly,emetineinhibitsSARS‐CoV‐2replicationinvitro,
andasynergisticeffectbetweenthecombinationofremdesivirandemetinewasobserved
[265].Asanotheralkaloidcompound,lycorinewasstronglyabletodiminishthespread
andreplicationofhumancoronavirusOC43(HCoV‐OC43)inamousecentralnervous
system[264].Ithasalsobeenshownthattwoalkaloidslycorineandoxysophoridinepos‐
sesstheabilitytosuppressthereplicationofSARS‐CoV‐2invitro[266].Consequently,
tylophorine,anaturalalkaloid,hasshownpromisingbeneficialeffectsagainstcorona‐
virusporcinetransmissiblegastroenteritisvirus(TGEV)throughsuppressingJAK2me‐
diatedNF‐κBactivationrelatedtotheinflammatoryresponse.Italsoinhibitedviralrep‐
licationbyinterferingwiththeviralRNAcomplex[267].Asbroad‐spectrumantiviral
agents,tylophorinebasedderivativesalsoblockedSARS‐CoV‐2,withEC50valuesof2.5–
14nM[268].Suchresultsindicatedthepotentialoftylophorineasanoveltherapeutic
interventionforCOVID‐19infection.

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Inadditiontophenoliccompoundsandalkaloids,terpenoidscouldalsocontainaus‐
piciousnaturalplant‐derivedsecondarymetabolitesforcombatingCOVID‐19[269].Asa
triterpenoidcompound,glycyrrhizinhasbeensuccessfullyappliedtomitigatevirus‐in‐
ducedinflammatorycascadesandviralreplication[270,271].Ithasbeenwell‐established
thathigh‐mobilitygroupB1(HMGB1)proteinplaysakeyroleinviralinfectionandrep‐
lication[272,273].Interestingly,aninsilicostudyperformedbyBaillyetal.revealedthat
glycyrrhizinisapotentialbinderofHMGboxprotein,andcouldtherebybeapromising
candidatetobeevaluatedagainstCOVID‐19[274].Cumulativeevidencehasdemon‐
stratedthatnaturalcoumarincompoundspossessantioxidant,antiapoptosis,andanti‐
inflammatoryactivitiestowardantiviraleffects.Additionally,theseagentseffectivelydis‐
ruptvariousstagesinthevirusreplicationcycle,andcouldtherebybebeneficialagents
fortacklingSARS‐CoV‐2[275].Regardingcoumarins,arecentinsilicostudyrevealedthat
somenaturallyoccurringcoumarins,includingcorymbocoumarin,methylgalbanate,and
heraclenol,displayedpotentialantiviralactivitythroughinhibitingMpro[276].Molecular
dockingapproachesindicatedthatnaturalcoumarincompoundtoddacoumaquinone
possessesasignificantsuppressingabilityagainstMproofSARS‐CoV‐2,whichisnecessary
forviralreplication[277].Anotherinsilicostudyalsoillustratedthatthebioactivecou‐
marininophyllumAremarkablytargetsMpro[278].
Consequently,ofothernaturalproducts,carotenoidsseemtobeofpotentialinterest
intargetingvariousstepsofthevirallifecycleandhostproteins[279].Asoneofthemost
potent/efficientcarotenoids,astaxanthinhasbeenapromisingsourceofantioxidationand
anti‐inflammatoryagents,withpromisingpotentialtocombatviralinfectionsandrelated
complicationsthroughtargetingseveraldestructivesignalingmediators[191].
Altogether,severalfindingsrevealedthatphytochemicalspossesstheabilitytosup‐
pressSARS‐CoV‐2infection.Unfortunately,almostallofthecurrentevidencefocusedon
theefficacyofphytoactivecompoundsinsilicoandinvitromodelsofCOVID‐19,andthe
mainantiviralmechanismsremainelusive.Therefore,thebeneficialeffectsofphytochem‐
icalagainstCOVID‐19andmainmechanismsrequirein‐depthresearchtobeverifiedby
preclinicalandclinicalstudies.Toxicologicalaspects,pharmacokineticsandpharmacody‐
namicspropertiesandpossiblesideeffects,andstructure–activityrelationship(SAR)
analysesneedappropriateassessment.
Insilicostudiesindicatedlimonin[280],berberine[281],andfisetin[282]inhibited
ACE2andspikeprotein[280],boundtoACE2,andincreasedNrf2,HO‐1,andTGF‐β
[281];alsoledtothereductionofTNF‐α,IL‐6,IL‐1β [282].Othercompoundssuchas
tetrandrine,lycorine,kazinolA[283],andsinigrin[284]inhibitedtheearlystageinHCoV‐
OC43‐infection,andalsoinhibitedtheeffectsagainstdifferentspeciesofCoV[283],as
wellasinhibitedSARS‐CoV3CLproandPLpro[283,284].Theresultsofinsilicostudiesalso
demonstratedthatmethylrosmarinate,calceolariosideB,myricetin3‐O‐beta‐D‐glucopy‐
ranoside,betulinicacid,cryptotanshinone,dihomo‐γ‐linolenicacid,kaempferol,querce‐
tin,sugiol,licoleafol,andamaranthinemayhavestrikingpotentialagainstCOVID‐19
[285,286].Basedoninsilicoevidence,differentflavonoids,likelytomentinA‐E[287],chry‐
sin[288],narcissin[289],cyaniding[290],andhesperetin[291],interactedwithACE2and
declineditsneurologicalmanifestationinCOVID‐19[288–291],andalsoinhibitedpapain‐
likeproteaseinCOVID‐19[287].Dockingevidenceindicatedthatbaicalinbindsto
TMPRSS2andleadstotheinhibitionofCOVID‐19[204].Aninvitrostudyalsoindicated
thatgeraniolhasinhibitoryeffectsagainstviralspikeproteinandisausefulagentfor
therapyagainstCOVID‐19[292].Additionally,othernaturalcompoundshaveimportant
rolesinmodulatingthosesignalingpathways,suchasmalvidin,whichleadstothere‐
ductionofBax/Bcl‐2,caspase‐3, IL‐β, andTNF‐α [50].Additionally,ostholealleviated
lunginjuryandinflammationthroughpreventingthedownregulationofACE2and
Ang1–7expression,therebypossessinganti‐inflammatoryeffects[293].Moreover,dai‐
dzeinreducedTLR4,MyD88,NF‐κB,MPO,IL‐6,andTNF‐α[294],thymolreducedthe
levelofNF‐κB,IL‐6,TNF‐α,andIL‐1β[295],hyperinreducedTNF‐α,IL‐6,IL‐1β,andNF‐
κB[296],andcannabidioldeclinedthelevelsofMPO,TNF‐α,andIL‐6[297].Thesenatural

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productsdeclinedthelevelofimportantmediatorsinsignalingpathwaysofCOVID‐19,
and haveavitalfunctioninreducingthesymptomsofCOVID‐19 .Severalphytochemicals
withpromisingantiviraleffectsarepresentedinTable1.Figure1showstheproposed
targetsandrelatedtherapeuticcandidatesforSARS‐CoV‐2.
Table1.Candidatephytochemicalswithpromisingantiviraleffects.
Phytochemical CompoundStudyTypeMechanismofAntiviralActivityReferences
Alkaloid
10′‐hydrox‐yusambarensineInsilico↓RdRp[263]
Berberine Invitro,Insilico
Antiviraleffect,↓ACE2,spikeproteinand
increasedNrf2,HO‐1
↓TGF‐β1,ROS
[281]
CryptospirolepineInsilico↓RdRp[263]
Emetin Invitro
↓Viralentry
↓MERS‐CoVS‐mediatedinfection,↓SARS‐
CoV‐2replication
[264,265]
Lycorine
Invivo
Invitro
↓SpreadandreplicationofHCoV‐OC43,
↓SARS‐CoV‐2replication[264,266]
Invitro↓DifferentspeciesofCoV[283]
OxysophoridineInvitro ↓SARS‐CoV‐2replication [266,298]
StrychnopentamineInsilico↓RdRp[263]
TetrandrineInvitro↓HCoV‐OC43‐infected[283]
TylophorineInvitro ↓JAK2,↓NF‐κB,↓inflammation,
↓replication [267,268]
AnthocyaninMalvidinInvitro↓Bax/Bcl‐2,Caspase‐3, IL‐1
β
, TNF‐α [50]
CannabinoidCannabidiol Invitro↓MPO,TNF‐α,IL‐6[297]
Coumarin
InophyllumAInsilico↓Mpro,↓replication[278]
MethylgalbanateInsilico↓Mpro,↓replication[276]
Osthole Invitro↓IL‐6,TNF‐α,
↑ACE2andAng1–7[293]
ToddacoumaquinoneInsilico↓Mpro,↓replication[277]
DiarylheptanoidHirsutenoneInvitro↓PLpro,↓replication[260]
Flavonoid
BaicaleinInvitro
Invivo
↓3CLpro↓VeroE6cellsdamage,↓lesionsof
lungtissue,↓replication,↓IL‐1β,↓TNF‐α,
↓inflammation
[245,246]
BiochaninAInsilico↓spikeglycoprotein[247]
KaempferolInvitro
Insilico↓3CLpro,↓replication[299]
LuteolinInvitro
Insilico
↓Viralentry↓SARS‐CoVinfection
↓TNF‐α,IL‐1β,IL‐6,IL‐18,NF‐κB[256,300]
Naringenin Invitro
Insilico
↓TPC2,↓viralinfection
↓TNF‐α,IL‐1β,IL‐6,IL‐18,NF‐κB [251,300]
NaringinInsilico↓Mpro,↓replication[249]
Insilico↓Spikeglycoprotein[248]
SilibininInsilico↓RdRp[255]
SilymarinInsilico
↓ACE2
↓IL‐6,IL‐1β,TNF‐α,p46‐p54,p42,p38,
p44,NF‐κB,andJNK.
[247]
TaxifolinInsilico↓Mpro[253]
Flavonoid 
CyanidinInsilico↓ACE2andRdRp[290]
KazinolAInvitro↓SARS‐CoV3CLproandPLpro[283]
Narcissin InsilicoBindtoACE2  [289]
TomentinA‐E Insilico↓PLproinCOVID‐19[287]

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Flavone
Baicalin Insilico↓TMPRSS2andleadtoinhibitionof
COVID‐19[204]
Chrysin Insilico↓ACE2anddeclineneurological
manifestationinCOVID‐19[288]
Flavonol
Fisetin Invitro,Insilico
↓ACE2,
↓TNF‐α,IL‐6,IL‐1β,
↑Nrf2,GPx,SOD
[282]
HesperetinInvitro↓ACE2andreduceneurologicalsignin
COVID‐19[291]
HesperetinInvitro↓ACE2andreduceneurologicalsignin
COVID‐19[291]
Hyperin Invitro↓TNF‐α,IL‐6,IL‐1β,NF‐κB[296]
Isoflavone Daidzein Invitro↓TLR4,MyD88,NF‐κB,MPO,IL‐6,TNF‐α [294]
Polyphenol
Catechin Insilico↓Spikeprotein,↓viralentry,↓ACE2[243]
Curcumin Insilico↓spikeprotein,↓viralentry,↓ACE2
↓TNF‐α,IL‐1β,IL‐6,IL‐18,NF‐κB,COX‐2[242,243,301]
Ellagicacid Invitro↓Mpro,↓replication[302]
Resveratrol Invitro ↓SARS‐CoV‐2infection.[258,301]
SinigrinInvitro↓SARS‐CoV3CLpro[284]
Terpenoid
CarvacrolInsilico↓Spikeprotein [292]
GeraniolInvitro↓Spikeprotein,
↓TNF‐α,IL‐1β,IL‐6,iNOS,COX‐2[292]
Limonin Insilico↓ACE2,3CLpro,PLpro,RdRpandspike
protein[280]
Thymol Invitro↓NF‐κB,IL‐6,TNF‐α,IL‐1β,
↑SOD[295]
ACE2:angiotensin‐convertingenzyme2;Bcl‐2:B‐celllymphoma2;COX‐2:cycloox‐
ygenase;ERK:extracellular‐regulatedkinase;GPx:glutathioneperoxidase;HCoV:human
coronavirus;HO‐1:hemeoxygenase‐1;IL:interleukin;iNOS:induciblenitricoxidesyn‐
thase;JAK:Januskinase;JNK:c‐JunN‐terminalkinase;Mpro:mainprotease;MERS‐CoV:
MiddleEastrespiratorysyndromecoronavirus;MIP:macrophageinflammatoryprotein;
MPO:myeloperoxidase;NF‐κB:nuclearfactor‐kappaB;PLpro:papain‐likeprotease;RdRp:
RNA‐dependentRNApolymerase;Nrf2:nuclearfactorerythroid2‐relatedfactor2;ROS:
reactiveoxygenspecies;SARS‐CoV‐2:severeacuterespiratorysyndromecoronavirus2;
SOD:superoxidedismutase;TGF‐β:tumorgrowsfactor‐β;TLRs:toll‐likereceptors;TNF‐
α:tumornecrosisfactor‐α;TPC2:two‐porechannel2.

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Figure1.MultipledysregulatedpathwaysinCOVID‐19.ACE2:angiotensin‐convertingenzyme2;Atg:autophagyrelated;
Bcl‐2:B‐celllymphoma2;CAT:catalase;COX:cyclooxygenase;GST:glutathioneS‐transferases;HO:hemeoxygenase;
IFN:interferon;IKKβ:IκBkinaseβ;IL:interleukin;JAK:Januskinase;LC3:lightchain3;NF‐κB:nuclearfactorkappaB;
RdRP:RNA‐dependentRNApolymerase;RTK:receptortyrosinekinase;STAT:signaltransducerandactivatoroftran‐
scription;TMPRSS2:transmembraneproteaseserine2;TNF‐α:tumornecrosisfactor‐α.
8.Discussion
DuetothecomplexpathologicalmechanismsbehindCOVID‐19,revealingitsprecise
signalingpathwaysmayopennewroadsforprovidingefficienttherapies.COVID‐19em‐
ploysvarioussignalingpathways/mediators,includinginflammation,oxidativestress,
apoptotic,andautophagy,toovercometheimmunesystem.Ithasalsobeenshownto
altertheexpressionofsomehostfactors,includingenzymes/mediatorsandco‐receptors
suchasACE2,aswellasILs,TNF‐α,IFN‐γ,Nrf2,Bax/caspases,andBeclin/LC3tofacili‐
tatecellularinfectionandsubsequentcomplications(Figure2).Despiteadvances,medic‐
inaltherapyagainstCOVID‐19remainschallenging.Besides,consideringthemultiple
mediatorsinvolvedinthepathogenesisofCOVID‐19,andprovidingmulti‐targetagents,
couldbeamoreserioussteptowardcontrollinganinfection.Wepreviouslyreportedthe
conventionaltherapeuticagentswhichpotentiallytargettheinflammatorysignaling
pathwaysinCOVID‐19[124].Thecurrentreviewintroducescandidatetherapeutictar‐
gets/treatmentinCOVID‐19,aswellastheevidenceofusingcandidatephytochemicals.
Inthisregard,phenoliccompounds,alkaloids,terpenoids,coumarins,andcarotenoids

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showedpotentialanti‐SARS‐CoV‐2effectsbytargetingvirallifecycle,virusentry/repli‐
cation,spikeproteins,ACE2,RdRP,PLpro,andMpro.Itisworthmentioningthat,despite
preclinicalmechanisticstudiesontheeffectsofphytochemicalsonSARS‐CoV‐2,more
clinicalinvestigationsareneededtoconfirmtheresults.Morestudies/methodsarealso
neededtodesignanoveldrugdeliverysystemthatcounteractsthepharmacokineticlim‐
itationsofphytochemicalsinCOVID‐19.
FurtherareasofresearchonnovelpathophysiologicalsignalingpathwaysofCOVID‐
19,especiallyoninflammatory,oxidativestress,apoptotic,andautophagicpathways,will
showmorepotentialcandidatesinthemanagement,prevention,andtreatmentof
COVID‐19complications.Thatsaid,morereportsarestillneededtoconfirmthebenefits
oftargetingtheaforementionedpathwaysinCOVID‐19.

Figure2.TheproposedtargetsandrelatedtherapeuticcandidatesinSARS‐CoV‐2.Atg:autophagy‐related;CAT:catalase;
CQ:chloroquine;HCQ:hydroxylchloroquine;GST‐1α:glutathiones‐transferases‐1α;HO‐1:hemeoxygenase;IFN:inter‐
feron;IL:interleukin;JAK/STAT:Januskinase(JAK)/signaltransducerandactivatoroftranscription(STAT);LC3:light
chain3;NF‐κB:nuclearfactorkappaB;ROS:reactiveoxygenspecies;RTK:receptortyrosinekinase;SARS‐CoV‐2:severe
acuterespiratorysyndromecoronavirus2;SOD:superoxidedismutase;TNF‐α:tumornecrosisfactor‐α.
AuthorContributions:Conceptualization,S.F.,M.H.F.andJ.E.;draftingofthemanuscript,S.F.,
Z.N.,S.Z.M.andS.P.;software,S.F.,reviewingandeditingofthepaper:S.F.,Z.N.,E.K.A.,M.H.F.,
E.S.‐S.andJ.E.;Allauthorshaveread,revisedandagreedtothepublishedversionofthemanu‐
script.Allauthorshavereadandagreedtothepublishedversionofthemanuscript.
Funding:J.E.gratefullyacknowledgesfundingfromCONICYT(PAI/ACADEMIAN°79160109).
InstitutionalReviewBoardStatement:Notapplicable.
InformedConsentStatement:Notapplicable.
ConflictsofInterest:Theauthorsdeclarethattheresearchwasconductedintheabsenceofany
commercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest.
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