Summaryof10ApprovedCOVID-19Small MoleculeDrugs
CoronaVirusDisease2019(COVID-19),adiseasecausedbytheSevere AcuteRespiratorySyndromeCoronavirus2(SARS-CoV-2),hashada devastatingimpactontheworld'spopulationandisthemostseriousglobal healthcrisissincethe1918influenzapandemic.Sincebeingdeclaredaglobal pandemicbyWHOon11March2020,thevirushascontinuedtothreatenthe healthofpeopleworldwide.
TheCOVID-19outbreakhasbecomeaglobalcrisisthathaskilledmorethan6 millionpeopleworldwideItwreakshavoconsocietiesandeconomies,andso far,theneedforeffectivetherapiesforCOVID-19remainshigh.Aspeople's understandingofthestructure,functionandpathogenicprocessesofthenovel coronavirushasimproved,manysmallmoleculedrugswithpotentialtofight COVID-19havebeendeveloped
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COVID-19iscausedbySARS-CoV-2SARS-CoV-2isabetacoronaviruswith apositive-sensesingle-strandedRNAgenomecontaining14openreading frames(ORFs)TwoORFsencodethepolymerinsPP1aandPP1bThefour ORFsencodeaseriesofstructuralproteins,includingspikeprotein(S), membraneprotein(M),envelopeprotein(E),andnucleocapsidprotein(N).
TheSproteinrecognizeshumanACE2receptorsandiscleavedbyhost proteases,responsibleforviralbindingandentryintohostcells.Mpro(major proteases)andPLpro(papainlikeproteases)areessentialfortheproduction andfunctionofnon-structuralproteins(NSPs).
SARS-CoV-2genomeanditsstructurediagram
ThegenomesizeofSARS-CoV-2iscloseto30kbItcontains14openreadingframes (ORFs)andencodes29proteinsTwooftheseORFs,accountingforabouttwo-thirdsof thegenome,encodetwopolymericproteins,whicharehydrolyzedbytheMprotease (Mpro)andpapainlikeprotease(PLpro)into16non-structuralproteins(nsps)(Source: Reference2)
Afterthenovelcoronavirusinvadescells,itbeginstoreplicateinlarge quantities;andthevirus'sRNA-dependentRNApolymerase(RdRp,also knownasnsp12)playsavitalroleinthesynthesisofthevirus'sgenetic material,RNA.WithRNApolymeraseasthecore,theviruswillcleverlyuse othercofactors(suchasnsp7/nsp8,etc)toassembleanefficientRNA synthesismachineforself-replication.Asthecorecomponentofthis replicationmachine,RNApolymeraseisoneofthemostimportantantiviral drugtargets.Destroyingthefunctionofthiscoredevicecanpreventthe replicationofthevirusandfinallyachievethepurposeoftreatmentTherefore, targetingthesefunctionalproteinsisareasonablestrategytoinhibitinfection andreplicationofCOVID-19
LifecycleofSARS-CoV-2
TheSARS-CoV-2SproteinrecognizestheACE2receptorandissimultaneouslycleaved byhostproteasesandentersthetargetcell,thenthegRNAisreleasedandtranslatedinto pp1aandpplb,whicharehydrolyzedintoNSPsnecessaryforviralreplicationCatalyzed byRdRp,newgRNAsaregeneratedandencodestructuralproteinstoassembleprogeny viruses(Source:Reference2)
Comparedwithbiologicalproductssuchasmonoclonalantibodiesandplasma products,smallmoleculesaremoreflexibleinbindingtotargetmolecules whenactingasantagonistsoragonists.Theirlowerproductioncostsand higherstabilityalsomakethemidealtherapeuticagentsforclinicaland researchapplications.Withtheincreasingunderstandingofthepathogenic mechanismofSARS-CoV-2infection,smallmoleculesfromnaturalsourcesor throughchemicalsynthesishaveshowntheirgreattherapeuticpotentialby interferingwithvariouspathwaysThedevelopmentofsmallmoleculesforthe treatmentofCOVID-19hasbeenachievedthroughmultiplestrategies, includingcomputer-aidedleadcompounddesignandscreening,natural productdiscovery,drugreuse,andcombinationtherapies
Accordingtoincompletestatistics,sofar,10small-moleculeCOVID-19 therapeuticdrugshavebeenapprovedorauthorizedglobally
Small-moleculeCOVID-19therapeuticshavedemonstratedtheirgreat potentialinthedevelopmentofanti-COVID-9therapies.However,thecurrent understandingofSARS-CoV-2andCOVID-9isonlythetipoftheiceberg,and itisnecessarytoimprovetheunderstandingofSARS-CoV-2andadeeper understandingofitslifecycleItisalsonecessarytocharacterizetheviral componentsinvolvedinitspathologicalprocess,andfurtherelucidatethe detailedmechanismofvirusreplicationandinteractionwithhostcellsinorder tobetterunderstandthevirus'destructionofthehostimmunesystem mechanism,soastofinddrugsthatarewelltargetedandmoreeffective
SeveralworrisomevariantssuchasAlpha(B.1.1.7),Delta(B.1.617.2),and Omicron(B11529)poseongoingchallengestothedrugdevelopment industry,andresistancecausedbyviralmutationsdrivesscientistscontinuing tosearchfornewcompounds,targets,anddrugcombinationstrategiesMore targetedantiviraldrugsaretheurgentneedsofhospitalizedpatientswith severesymptomsTheelderlyover65yearsofageandvulnerablepeoplewith
HuatengPharma https://ushuatengscicom underlyingdiseasesarestillthemostdeservingofspecialattention,anddrug developmentneedsspecialattention.
HuatengPharmaisaworldleadingsupplierdedicatedto providingpharmaceuticalintermediatesandPEGderivativestocustomers worldwideWecanprovidecustomsynthesisforcommercialscaleupof COVID-19oraldrugEnsitrelvir(S-217622)andPaxlovidintermediates.We canalsosupplymPEG-DTA(ALC-0159),mPEG-DSPE,mPEG-DMGand otherPEGproductswhichusedasexcipientsinCOVID-19vaccines.
PaxlovidIntermediates
CASNO67911-21-1Caronicanhydride
CASNO.194421-56-26,6-Dimethyl-3-Azabicyclo[3.1.0]hexane-2,4-dione
CASNO565456-77-1(1R,2S,5S)-Methyl6,6-dimethyl-3-azabicyclo[310] hexane-2-carboxylatehydrochloride
CASNO943516-54-96,6-Dimethyl-3-azabicyclo[310]hexane
CASNO.72748-35-7Lambda-cyhalothricacid
Ensitrelvir(S-217622)Intermediates
CAS
NO:1360105-53-83-Tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-d ione
CASNO.:1893125-36-46-Chloro-2-methyl-2H-indazol-5-amine
CASNO:135206-76-73-(Chloromethyl)-1-methyl-1H-1,2,4-triazole
CASNO.:157911-56-32,4,5-Trifluorobenzylbromide
CASNO:76-05-1 Trifluoroaceticacid
References:
[1].https://www.news-medical.net/news/20200702/Structure-of-the-full-SARS-CoV-2-RNA -genome-in-infected-cellsaspx
[2].Lei,S.,Chen,X.,Wu,J.etal.SmallmoleculesinthetreatmentofCOVID-19.Sig
TransductTargetTher7,387(2022)https://doiorg/101038/s41392-022-01249-8
[3].https://www.frontiersin.org/articles/10.3389/fphar.2022.899633/full.
[4]https://doiorg/1038207/JMCRCS/2021/0215220
[5].https://ijhmp.com/currentissue/Article%202,2,1.pdf
[6]https://wwwcnkicomcn/Article/CJFDTotal-GRKZ202012017htm
[7]https://wwwfrontiersinorg/articles/103389/fphar2022899633/full
[8]https://wwwmhlwgojp/stf/newpage29320html
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