Molnupiravir: Ib qho kev ua si hloov cov ntsiav tshuaj ntawm qhov ncauj rau kev kho mob ntawm COVID-19

Molnupiravir, ib qho nucleoside analog ntawm cytidine, ib qho tshuaj uas tau pom zoo ntawm qhov ncauj bioavailability thiab cov txiaj ntsig tau zoo hauv Phase 1 thiab Theem 2 kev sim, tuaj yeem ua pov thawj tias yog rab phom khawv koob ua yeeb yam los tiv thaiv kab mob SARS-CoV2 hauv tib neeg. Qhov zoo ntawm molnupiravir vis a vis uas twb muaj lawm txhaj tshuaj tiv thaiv kab mob yog tias nws tuaj yeem noj hauv qhov ncauj thiab tau pom tias tshem tawm tus kab mob SARS-CoV2 hauv 24 teev hauv kev tshawb fawb ua ntej hauv ferrets..

COVID-19 kev kis thoob qhov txhia chaw tau ua pov thawj tias yog kev dag ntxias thiab tsis paub txog thoob plaws ntiaj teb. Thaum lub teb chaws xws li United Kingdom tau maj mam rov qhib dua thiab so qhov kev kaw cia kom pom qhov tshwm sim tsawg zuj zus, Fabkis lub qhov rooj tom ntej tab tom ntsib nthwv dej thib peb thiab cov tebchaws xws li Is Nrias teb tam sim no tab tom ntsib kev kis tus kab mob loj tshaj plaws txawm tias tag nrho cov kev npaj thiab kev tsim peev txheej yav dhau los. ib xyoo. Txawm hais tias muaj ntau txoj kev kho mob tau sim tawm tsam COVID-19 xws li kev siv dexamethasone thiab siv cov tshuaj tiv thaiv kab mob xws li favipravir thiab remdesivir los tawm tsam tus kab mob, kev yos hav zoov tseem tab tom kho kom zoo nrog 239 cov tshuaj tiv thaiv kab mob hauv qab kev txhim kho. tsom rau cov theem sib txawv ntawm kab mob lub neej¹. Tsis tas li ntawd, lwm txoj hauv kev raug sim los tiv thaiv tus kab mob nkag mus rau hauv cov hlwb los ntawm kev cuam tshuam nrog nws txoj kev khi rau tus tswv tsev cell. Qhov no yog ua los ntawm kev tsim cov proteins uas khi rau cov kab mob sib kis kab mob yog li tiv thaiv nws cov kev cuam tshuam nrog ACE 2 receptor ntawm tus tswv tsev cell lossis tsim ACE 2 receptor decoys uas khi rau cov protein ntau ntawm tus kab mob thiab inhibits nws nkag mus rau hauv tus tswv tsev.  

Ob peb lwm cov tshuaj tau tsim los tsom cov kab mob sib kis uas tsim los thaum tus kab mob nkag mus rau hauv lub xov tooj ntawm tes, siv lub tshuab cellular thiab pib ua nws cov proteins ntxiv los siv lawv rau genome replication thiab thaum kawg ua cov kab mob ntau dua. Ntawm ntau cov proteins, lub hom phiaj tseem ceeb ntawm cov protein yog RNA-dependent RNA polymerse (RdRp) uas theej RNA. Cov kws tshawb fawb tau siv ntau yam nucleoside thiab nucleotide analogs los ua kom yuam kev RdRp rau hauv kev koom ua ke rau hauv cov kab mob RNA uas nws thiaj li cuam tshuam RdRp thiab nres cov kab mob sib kis. Ob peb cov analogs tau siv xws li favipiravir thiab triazavirin, ob qho tib si tsim los tiv thaiv kab mob khaub thuas; ribavirin, siv rau cov kab mob ua pa syncytial thiab kab mob siab C; galidesivir, txhawm rau thaiv kev rov ua dua ntawm Ebola, Zika, thiab kab mob daj daj; thiab remdesivir, thawj zaug siv tawm tsam tus kab mob Ebola. 

Txawm hais tias kev txhaj tshuaj tiv thaiv muaj qee qhov kev cia siab hauv daim ntawv ntawm kev txo qis tus kab mob hnyav thaum kis tus kab mob, nws tseem tsis tiv thaiv kev kis tus kab mob. Tib neeg tseem tuaj yeem kis tau tus kab mob txawm tias tom qab txhaj tshuaj tiv thaiv zoo uas yog qhov laj thawj zoo txaus kom ceev nrooj nrhiav cov tshuaj tiv thaiv kab mob.¹, ob qho tib si dav spectrum thiab ib qho tshwj xeeb (tsuas yog txoj kev uas peb muaj cov tshuaj tua kab mob tiv thaiv kab mob). Ntawm qhov hais tsis ntev los no yog cov tshuaj hu ua Molnupiravir, ib qho nucleoside analog ntawm cytidine, uas tuaj yeem noj qhov ncauj thiab tau pom tias tiv thaiv tus kabmob coronavirus. Denison thiab cov npoj yaig tau tshaj tawm tias molnupiravir txo qis kev rov ua dua ntawm ntau tus kabmob coronaviruses, suav nrog SARS-CoV-2, hauv cov nas.². Nws tau pom tias yuav txo tau cov kab mob sib kis 100,000-fold hauv cov nas tsim kom muaj tib neeg lub ntsws cov ntaub so ntswg³. Nyob rau hauv cov ntaub ntawv ntawm ferrets, molnupiravir tsis tsuas yog txo cov tsos mob, tab sis kuj coj mus rau xoom kab mob kis nyob rau hauv 24 teev.⁴. Cov kws sau ntawv ntawm txoj kev tshawb fawb no tau lees tias nws yog thawj zaug ua qauv qhia ntawm cov tshuaj muaj nyob hauv qhov ncauj uas cuam tshuam SARS-CoV-2 sai. Qhov tseem ceeb tshwj xeeb yog tias kev kho mob molnupiravir tiv thaiv tus kab mob kis mus rau cov neeg tsis tau txais kev kho mob ncaj qha txawm hais tias muaj kev sib txuas ncaj qha mus ntev ntawm qhov chaw thiab tiv tauj cov tsiaj. Qhov kev thaiv tag nrho no tuaj yeem pab tiv thaiv kev sib kis tau zoo SARS-CoV-2 kab mob vais lav. Hauv lwm qhov kev tshawb fawb hauv tsev kho mob hauv hamsters, molnupiravir, ua ke nrog favipiravir tau pom tias muaj kev sib xyaw ua ke ntawm kev txo qis ntawm cov kab mob ntau dua li kev kho nrog molnupiravir thiab favipiravir ib leeg.⁵.  

Ib qho randomized, ob-dig muag, tshuaj placebo-tswj, First-in-Human txoj kev tshawb fawb tsim los soj ntsuam kev nyab xeeb, kam rau ua, thiab pharmacokinetics ntawm molnupiravir tom qab kev tswj hwm qhov ncauj rau cov neeg ua haujlwm noj qab haus huv hauv tag nrho ntawm 130 yam qhia tau hais tias molnupiravir tau ua tib zoo zam yam tsis muaj qhov tseem ceeb. xwm txheej phem^6,7. Raws li cov kev tshawb pom no, kev tshawb fawb Theem 2 tau ua nyob rau hauv 202 cov neeg mob uas tsis nyob hauv tsev kho mob thiab pom tias muaj tus kab mob sib kis sai dua ntawm cov tib neeg thaum ntxov. Covid-19 kho nrog molnupiravir. Cov txiaj ntsig no tau cog lus thiab yog tias muaj kev txhawb nqa los ntawm cov kev tshawb fawb ntxiv theem 2/3⁸ uas tab tom ua tsis tu ncua thiab theem 3 cov kev tshawb fawb uas tau muab ua ntej tuaj yeem muaj qhov cuam tshuam tseem ceeb hauv kev kho mob thiab tiv thaiv kev kis tus kab mob SARS-CoV-2, uas txuas ntxiv kis thiab hloov mus rau feem ntau ntawm cov tebchaws thoob plaws ntiaj teb. Yog tias molnupiravir qhia tau tias muaj txiaj ntsig zoo hauv cov kev sim uas tau hais los saum toj no, nws yuav lav qhov loj thiab cov txheej txheem tsim tau zoo los tsim nws ntau ntau. Cov kev tshawb fawb tsis ntev los no los ntawm Jamison thiab cov npoj yaig tau piav qhia txog chromatography dawb enzymatic ob-kauj ruam txheej txheem ntawm kev ua molnupiravir los ntawm cytidine, thawj kauj ruam koom nrog enzymatic acylation tom qab transamination kom tau txais cov khoom siv tshuaj kawg.⁹. Qhov no yuav muaj txiaj ntsig tshwj xeeb thaum nthuav tawm cov khoom siv tshuaj rau kev lag luam siv los tsim cov txheej txheem siv nyiaj kom muaj txiaj ntsig zoo los pab kom muaj cov tshuaj muaj txiaj ntsig ntawm tus nqi pheej yig rau cov teb chaws cuam tshuam tshwj xeeb tshaj yog cov teb chaws tsim thiab tsis muaj kev tsim kho. 

***

References  

1. Service R., 2021. Ib tug hu rau caj npab. Science.  12 Mar 2021: Peb. 371, Is Taws Nem 6534, pp. 1092-1095. DOI: https://doi.org/10.1126/science.371.6534.1092 

2. Sheahan TP, Sims AC, Zhou S, Graham RL et al. Ib qho kev hais lus bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 nyob rau hauv tib neeg txoj hlab ntsws epithelial cell kab lis kev cai thiab ntau tus kab mob coronaviruses hauv nas. Kev txhais lus Science Tshuaj kho mob. 29 Plaub Hlis 2020: Vol. 12 Ib., 541, 5883. DOI: https://doi.org/10.1126/scitranslmed.abb5883  

3. Wahl, A., Gralinski, LE, Johnson, CE et al. Tus kab mob SARS-CoV-2 tau kho tau zoo thiab tiv thaiv los ntawm EIDD-2801. xwm 591, 451-457 (2021). https://doi.org/10.1038/s41586-021-03312-w 

4. Cox, RM, Wolf, JD & Plemper, RK Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. leej Microbiol 6, 11-18 (2021). https://doi.org/10.1038/s41564-020-00835-2  

5. Abdelnabi R., Foo C., et al 2021. Kev kho ua ke ntawm Molnupiravir thiab Favipiravir ua rau muaj kev muaj peev xwm ua tau zoo hauv tus qauv SARS-CoV2 hamster tus kab mob los ntawm kev nce zaus ntawm kev hloov pauv hauv cov kab mob genome. Ua ntej. BioRxiv. Tshaj tawm Lub Peb Hlis 01, 2021. DOI: https://doi.org/10.1101/2020.12.10.419242 

6. Painter W., Holman W., thiab al 2021. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2. Antimicrobial Agents thiab Chemotherapy. Luam tawm online Lub Plaub Hlis 19, 2021. DOI: https://doi.org/10.1128/AAC.02428-20  

7. ClinicalTrial.gov 2021. Ib qho Randomized, Ob-dig muag, Placebo-Controlled, First-in-Human Study Designed to evaluate the Safety, Tolerability, and Pharmacokinetics of EIDD-2801 Following Oral Administration to Healthy Volunteers. Sponsor: Ridgeback Biotherapeutics, LP. ClinicalTrials.gov Identifier: NCT04392219. Muaj nyob online ntawm https://clinicaltrials.gov/ct2/show/NCT04392219?term=NCT04392219&draw=2&rank=1 Tau txais los ntawm 20 Plaub Hlis 2021.  

8. ClinicalTrial.gov 2021. A Theem 2/3, Randomized, Placebo-Controlled, Double-Diglind Clinical Study los soj ntsuam qhov ua tau zoo, kev nyab xeeb, thiab tshuaj kho mob ntawm MK-4482 hauv cov neeg laus uas tsis yog tsev kho mob nrog COVID-19. Tus Txhawb Nqa: Merck Sharp & Dohme Corp. ClinicalTrials.gov Tus ID: NCT04575597. Muaj nyob online ntawm https://clinicaltrials.gov/ct2/show/NCT04575597?term=Molnupiravir&cond=Covid19&draw=2&rank=2 . Tau txais los ntawm 05 May 2021. 

9. Ahlqvist G., McGeough C., thiab al 2021. Kev nce qib mus rau qhov loj-Scale Synthesis ntawm Molnupiravir (MK-4482, EIDD-2801) los ntawm Cytidine. ACS Omega 2021, 6, 15, 10396–10402. Hnub Tshaj Tawm: Plaub Hlis 8, 2021. DOI: https://doi.org/10.1021/acsomega.1c00772 

***