Insight Into SARS-CoV-2 Omicron Variant Immune Escape Possibility And Variant Independent Potential Therapeutic Opportunities Part 2
May 30, 2023
4. Cov txheej txheem ntawm kev tiv thaiv kab mob tiv thaiv kab mob los ntawm COVID-19 tshuaj tiv thaiv
Ntau cov tshuaj tiv thaiv tau tsim thiab muab tshuaj rau kev tiv thaiv thiab kho lub hom phiaj tiv thaiv kab mob SARS-CoV-2. Plaub qhov tshuaj tiv thaiv tau pom zoo los ntawm US Food and Drugs Administration (FDA) rau kev siv thaum muaj xwm txheej ceev suav nrog BNT162b2 tsim los ntawm Pfizer-BioNTech, mRNA1273 los ntawm Moderna, thiab Ad26.COV2.S los ntawm Johnson & Johnson (J & J), thiab ChAdOx1 los ntawm AstraZeneca [70,71,72,73,74,75,76]. Lwm cov tshuaj tiv thaiv kuj tseem siv tau thiab ntau ntxiv tseem tab tom txhim kho. Feem ntau cov tshuaj tiv thaiv tau pom los txhawb kev tiv thaiv kab mob thiab, qhov tseem ceeb tshaj, txo cov kab mob COVID{16}}, mus pw hauv tsev kho mob, thiab tuag hauv kev sim tshuaj [70,71,72, 73].
Cov tshuaj tiv thaiv no siv mRNA ntawm S-protein ua qauv rau tus kab mob SARS-CoV-2. Pfizer thiab Moderna ob leeg siv lipid nanoparticles (LNPs) [77,78], thiab J & J thiab AstraZeneca siv adenoviruses [75,79,80] ua lub tsheb xa khoom muaj zog thiab ntau yam. Extracellular mRNA yog nkag tau yooj yim los ntawm RNase hauv cov ntaub so ntswg, uas yog vim li cas cov tshuaj tiv thaiv RNA liab qab tsis ua tiav [81]. Tus kab mob adenovirus muaj ob-stranded DNA uas tau hloov mus rau hauv mRNA thiab thaum kawg tau muab txhais ua cov protein. Cov khoom xyaw nquag ntawm txhua qhov tshuaj tiv thaiv yog mRNA. Cov tshuaj tiv thaiv J & J thiab AstraZeneca pib ib kauj ruam ua ntej Pfizer thiab Moderna. Lub hom phiaj kawg yog tib yam, txawm li cas los xij, ua rau S-protein. Vim tias cov txheej txheem tshwj xeeb ntawm cov tshuaj tiv thaiv kab mob tiv thaiv kab mob tiv thaiv COVID-19 tam sim no nkag siab tsis tiav, Kuv tau piav qhia txog cov txheej txheem dav dav ntawm kev txhaj tshuaj tiv thaiv kab mob tiv thaiv kab mob, uas kuj tseem siv tau rau SARS-CoV-2 kab mob . Daim duab schematic uas muab cov ntsiab lus ntawm cov tshuaj tiv thaiv lub cev tiv thaiv kab mob tau nthuav tawm hauv daim duab 1.
Kev sib raug zoo ntawm mRNA thiab kev tiv thaiv kab mob cuam tshuam nrog lub luag haujlwm ntawm mRNA hauv lub cev tiv thaiv kab mob. Thaum lub sij hawm tiv thaiv kab mob, lub cev tiv thaiv kab mob tsim muaj ntau yam kev taw qhia cov molecules thiab cov proteins, suav nrog ntau hom mRNA. mRNA plays lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob, nws tuaj yeem tswj cov noob qhia ntawm cov hlwb, yog li cuam tshuam rau kev nce qib thiab qhov tshwm sim ntawm kev tiv thaiv kab mob.
Tshwj xeeb, mRNA tuaj yeem koom nrog hauv kev tswj hwm lub cev tiv thaiv kab mob hauv ntau txoj hauv kev, xws li:
1. mRNA encoding signaling molecules: Lub cev tiv thaiv kab mob tuaj yeem ua ke ntau yam ntawm cov cim taw qhia los ntawm mRNA, xws li cytokines thiab chemokines, uas tuaj yeem cuam tshuam rau lwm yam kev tiv thaiv kab mob, yog li txhawb lossis inhibiting lub cev tiv thaiv kab mob.
2. Kev tswj hwm kev hloov pauv: mRNA tuaj yeem cuam tshuam rau theem ntawm cov noob caj noob ces qhia los ntawm kev tswj hwm kev hloov pauv, yog li cuam tshuam rau lub cev tiv thaiv kab mob. Piv txwv li, qee cov mRNAs tswj cov tshuaj tiv thaiv kab mob ntawm lub cev tiv thaiv kab mob.
3. Kev cai txhais lus: Cov txheej txheem kev txhais lus thiab kev txhais lus ntawm mRNA kuj yuav raug tswj los ntawm lub cev tiv thaiv kab mob. Piv txwv li, hauv cov kab mob tiv thaiv kab mob, cov mRNA tshwj xeeb tuaj yeem xaiv tau muab txhais ua cov proteins, yog li tswj hwm kev loj hlob ntawm lub cev tiv thaiv kab mob.
Hauv cov ntsiab lus, mRNA ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob, thiab nws tuaj yeem cuam tshuam rau kev nce qib thiab cov txiaj ntsig ntawm kev tiv thaiv kab mob, yog li cuam tshuam rau lub cev muaj peev xwm tiv thaiv kab mob. Yog li ntawd, kev kawm txog kev tswj hwm ntawm mRNA thiab nws txoj haujlwm hauv kev tiv thaiv kab mob yuav pab kom nkag siab txog kev ua haujlwm ntawm lub cev tiv thaiv kab mob thiab muab cov tswv yim tshiab rau kev kho mob thiab tiv thaiv kab mob. Los ntawm qhov kev xav no, peb yuav tsum xyuam xim rau kev txhim kho peb txoj kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv zoo. Cistanche yog nplua nuj nyob rau hauv ntau yam tshuaj antioxidant, xws li vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals thiab txo oxidation. Kev ntxhov siab, txhim kho kev tiv thaiv ntawm lub cev.
Nyem cistanche deserticola ntxiv
Cov tshuaj tiv thaiv kab mob COVID-19 tau txhaj tshuaj intramuscularly rau hauv cov leeg deltoid kom muaj kev phom sij tsawg thiab feem ntau cov tshuaj tiv thaiv kab mob [82,83,84]. Cov nqaij deltoid muaj ntau lub hlwb, xws li cov leeg hlwb, fibroblasts, lub cev tiv thaiv kab mob, (feem ntau yog dendritic hlwb, DCs, thiab macrophages), thiab natural killer (NK) hlwb (Fig. 1A). Hauv cov tshuaj tiv thaiv J & J thiab AstraZeneca, tus kab mob adenovirus khi rau saum npoo ntawm tus tswv tsev cell thiab, tom qab ntawd, yog nyob rau hauv ib qho endosome uas cleaves viral plhaub thiab tso tawm DNA. Cov DNA no nkag mus rau hauv lub nucleus thiab tau hloov mus rau mRNA.
Qhov no mRNA ces tawm ntawm lub nucleus mus rau cytoplasm. Raws li nrog cov tshuaj tiv thaiv kab mob adenovirus, LNPs qhwv mRNA khi rau ntawm lub xovtooj ntawm tes thiab ua haujlwm sab hauv, tom qab ntawd rhuav tshem LNPs plhaub, thiab tso cov mRNA rau hauv cytoplasm (Fig. 1B). Dawb mRNA nyob rau hauv cytoplasm khi rau ribosome, lub tshuab me me uas khaws cov khoom siv caj ces thiab ua ke cov protein uas yog encoded hauv cov khoom siv caj ces. Ib lub xov tooj ntawm tes muaj peev xwm muaj txog 10 lab ribosomes thiab siv txog 60 feem pua ntawm nws lub zog ua ib qho protein, thiab 80 ntau hom proteins yog synthesized [85]. Hauv cov tshuaj tiv thaiv COVID-19, nws yuav tsim cov tshuaj S-protein. Tom qab tsim cov S-proteins, cov hlwb tsis cia lawv tawm, zoo li cov tshuaj hormone-secreting hlwb. Nyob rau hauv lub cell, S-proteins tau pub rau lwm lub tshuab me me hu ua proteasome, uas ua rau lawv tawg mus rau hauv me me. Cov me me ntawm S-proteins yog loaded ntawm cov proteins tshwj xeeb uas hu ua cov histocompatibility complexes. Muaj ob hom MHC, xws li MHC I thiab MHC II.
Txawm hais tias MHC kuv tau qhia los ntawm txhua lub hlwb, kev qhia ntawm MHC II tsuas yog txwv rau DCs thiab macrophages [86,87,88]. Cov hlwb no coj cov tshuaj tiv thaiv txawv teb chaws thiab nthuav tawm rau ntawm lawv qhov chaw thiab tom qab ntawd cuam tshuam nrog lwm lub cev tiv thaiv kab mob, hu ua 'professional' antigen-presenting cells (APCs). Cov khoom me me ntawm S-proteins raug thauj mus rau endoplasmic reticulum (ER) los ntawm cov channel hu ua transporter-associated antigen processing (TAP) qhov chaw uas lawv thauj mus rau nascent MHC I. Lub MHC kuv loaded S-protein mus rau lub cell membrane thiab tau nthuav tawm ntawm lub xovtooj ntawm tes raws li kev tswj hwm (Daim duab 1B). Thaum lawv tau nthuav tawm ntawm lub xov tooj ntawm tes, cytotoxic T (CD8 ntxiv) cov hlwb paub thiab khi rau MHC I- complex. Thaum khi rau MHC I complex ntawm T cell receptor (TCR) thiab CD8 protein, T cell ua kom qhib tau (Fig. 1C). Nyob rau hauv lub xub ntiag ntawm IL2, CD8 ntxiv rau cov hlwb secrete perforins thiab granzymes, ua rau cov leeg hlwb apoptosis thiab tawg. Thaum lub cell tawg, S-proteins thiab qee cov mRNAs raug tso tawm ntawm lub hlwb. S-proteins thiab mRNA yog tam sim ntawd phagocytized los ntawm APCs, tshwj xeeb, macrophages thiab DCs. Tom qab phagocytosis, macrophages tsim ib lub vesicle nyob ib ncig ntawm S-protein hu ua phagosome. Lub phagosome yog txuam nrog lysosome uas muaj cov kua qaub bleach uas ua rau S-protein. Ib zaug ntxiv lawm, S-proteins tau thauj khoom hauv ER uas ua rau MHC II. MHC II-S protein complex los ntawm ER thiab nkag mus rau hauv phagolysosome qhov twg S-proteins tau tawg ua me me. MHC II thiab S protein complexes txav mus rau ntawm lub xovtooj ntawm tes thiab tso tawm kom pom nyob rau hauv kev tswj hwm (Daim duab 1D). Tam sim no cov complex nyob rau hauv lub cev tiv thaiv kab mob (macrophage) txuas nrog naïve T hlwb los yog T pab (CD4 ntxiv) hlwb kom induce activation. Cov activated naïve T cells hloov mus rau hauv T helper 1 (Th1) cell lossis Th2 cell (Fig. 1E).
Txawm li cas los xij, cov neeg txiav txim siab ntawm Th1 thiab Th2 txoj hauv kev tseem tsis tau paub. Muaj ob peb lub tswv yim muaj nyob rau postulate txoj kev. PAMP thiab cytokine milieu hypotheses muaj xws li hom receptor khi rau cov kab mob / antigen los txiav txim seb hom kev tiv thaiv kab mob yuav tshwm sim. Muab qhov kev ua kom lub cev tiv thaiv kab mob hauv lub cev, tshwj xeeb tshaj yog macrophages, thiab DCs, tshwm sim los ntawm cov kab mob sib txuas nrog cov qauv (PAMPs). PAMP tau lees paub ncaj qha los ntawm tus tswv tsev qauv lees paub receptors (PRRs) thiab tus lej xov tooj zoo li tus neeg txais (TLRs). Yog tias TLRs khi rau cov kab mob, macrophages / DCs yuav sim ua rau Th1 txoj hauv kev. Ntawm qhov tod tes, yog tias PRRs koom nrog kev khi rau cov kab mob, txoj hauv kev Th2 yuav tshwm sim [89,90]. Tsis tas li ntawd, kev txiav txim siab kuj cuam tshuam los ntawm cov ntaub so ntswg. Tau kawg, thaum muaj kab mob tshwm sim, cov ntaub so ntswg yuav pib puas tsuaj thiab cov kab mob hauv zos yuav pib, thiab cov cytokines hauv zos, cov tshuaj chemokines raug tso tawm los ntawm cov txheej txheem inflammatory, xws li tab sis tsis txwv rau ILs, TNFs, thiab cov proteins kub poob siab. Cov kab mob tsis zoo T tsis paub tias yuav yog Th1 lossis Th2 txoj hauv kev.
Thaum macrophage txuas nrog lub hlwb tsis zoo, yuav tsum muaj costimulation nyob ntawm seb hom T cell receptors (TCR thiab PRR) lossis cytokines thiab chemokines muaj. Cov kab txuas txuas, macrophages, lossis DCs yuav txiav txim siab seb cytokines yuav cuam tshuam rau txoj hauv kev [90]. Piv txwv li, yog tias IL12 raug tso tawm rau hauv ib puag ncig thaum lub sijhawm ntawd, qhov tsis zoo T cell yuav nkag mus rau hauv txoj kev Th1 thiab yog tias IL4 raug tso tawm, lub naïve T cell yuav mus rau hauv txoj kev Th2. Muaj lwm txoj kev xav hu ua qhov pib hypothesis. Qhov no yog qhov tseem ceeb vim tias txoj hauv kev raug xaiv los ntawm koob tshuaj tiv thaiv lossis kev thauj khoom ntawm cov kab mob tshwm sim hauv qhov kev sib cuam tshuam ntawm macrophages nrog naïve T hlwb. Nws kuj tseem txiav txim siab tias yog vim li cas tus neeg lub cev tiv thaiv kab mob yog humoral piv rau cell-mediated immunity [90,91]. Qhov kev xav no tau hais tias, yog tias cov antigen tsawg dua, feem ntau tsis muaj lus teb. Yog hais tias tus nqi antigen los yog cov kab mob load yog nruab nrab, ces txoj kev Th2 yog coj uas yog txoj kev humoral tiv thaiv kab mob. Yog tias cov kab mob / antigen load siab dhau lawm, ces txoj kev Th1 raug xaiv uas yog txoj kev tiv thaiv kab mob ntawm tes. Nws tuaj yeem nyob ntawm qhov koob tshuaj tiv thaiv / kab mob los txiav txim siab seb hom kev tiv thaiv kab mob yuav ua haujlwm li cas.
Nyob rau hauv lub xub ntiag ntawm IL 4 thiab IL 5, Th2 cell activates B hlwb los hloov plasma hlwb uas tsim thiab secrete antigen-specific antibodies. Cov tshuaj tiv thaiv mus txhua qhov chaw los ntawm cov ntshav thiab neutralize cov kab mob tshwj xeeb thiab yog li muab cov tshuaj tiv thaiv kab mob humoral. Thiab nyob rau hauv lub xub ntiag ntawm IL2 thiab IL21, Th1 cell activates cytotoxic T hlwb los secrete perforins thiab granzymes uas ncaj qha tua cov kab mob hlwb, thiab yog li muab lub cell-mediated tiv thaiv teb (Daim duab 1E). Ob txoj hauv kev kuj tsim cov hlwb tshwj xeeb uas nyob ntev hu ua nco B thiab T hlwb rau kev tiv thaiv yav tom ntej.
Kev txo qis kev tiv thaiv kab mob tiv thaiv Omicron variant tau tshaj tawm hauv kev tshawb fawb siv cov qauv ntshav plasma los ntawm cov tib neeg uas muaj ob koob tshuaj tiv thaiv COVID-19 mRNA cov tshuaj tiv thaiv [92], thiab cov neeg mob yav dhau los SARS-CoV-2 kab mob [93] . Qhov no tsis tau txhais hais tias nws kuj suppresses T-cell-mediated tiv thaiv. Cov tshuaj tiv thaiv no tau raug tshaj tawm los ua kom muaj zog T cell-mediated immune teb uas ua rau muaj kev tiv thaiv tseem ceeb tiv thaiv kev mus pw hauv tsev kho mob lossis tuag [60,94,95,96] thiab zoo li, nws ua lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm SARS-CoV{{ 13}} kab mob, suav nrog omicron, tab sis lawv qhov tseem ceeb tau raug kwv yees tsis tau txog tam sim no. Ib yam li ntawd, kev tiv thaiv kab mob hauv lub cev muaj qhov nrawm thiab dav-spectrum ntawm kev ua haujlwm uas tseem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kev mob nkeeg, kev mus pw hauv tsev kho mob, thiab kev tuag ntawm cov neeg mob. Cov tshuaj tiv thaiv tuaj yeem saib ntawm ntau qhov kawg, lawv tuaj yeem tiv thaiv kev kis kab mob, kev sib kis, mus pw hauv tsev kho mob, thiab kev tuag mus rau qee qhov, tau kawg, thiab tsis muaj dab tsi yog 100 feem pua.
5. Omicron puas tuaj yeem tiv thaiv kev tiv thaiv los ntawm cov tshuaj tiv thaiv lossis kab mob yav dhau los?
Nrog rau qhov tshwm sim ntawm qhov hloov pauv tshiab ntawm SARS-CoV-2 vim qhov hloov pauv, cov tshuaj tiv thaiv uas tsim los ntawm cov tshuaj tiv thaiv uas twb muaj lawm yuav poob lub peev xwm los cuam tshuam cov kev hloov pauv sib txawv (148,149). Cov lus nug tseem ceeb tam sim no yog, qhov kev hloov pauv hauv omicron variants evasion tiv thaiv cov tshuaj tiv thaiv thiab / lossis kab mob yav dhau los li cas? Cov pov thawj yav dhau los rau kev tiv thaiv kev tiv thaiv, cov caj ces ntawm SARSCoV-2 txawv ntawm li 50 feem pua thiab 79 feem pua los ntawm nws cov kwv tij, Middle East Respiratory Syndrome coronavirus (MERS-CoV) thiab SARSCoV, feem. [97]. Kev hloov pauv 50 bps hauv Omicron txhais tau tias 0.167 feem pua ntawm cov kab mob caj ces txawv ntawm lawv cov poj koob yawm txwv, qhov feem pua ntawm kev hloov pauv me me dhau los tiv thaiv kev tiv thaiv. Ib txoj kab sib txawv ntawm cov pov thawj yog cov kab mob qhua pias thiab kab mob polio muaj qhov hloov pauv siab, qhia tias 95 feem pua ntawm cov tib neeg tseem muaj cov tshuaj tiv thaiv kab mob uas cuam tshuam cov kab mob no zoo heev nrog kev txhaj tshuaj [98,99]. Cov tshuaj tiv thaiv kab mob qhua pias tau nyob ib ncig ntawm 70 xyoo, thiab tshuaj tiv thaiv kab mob polio rau ib xyoo caum.
Raws li tau hais los saum toj no, S-protein, tus neeg nruab nrab ntawm tus tswv tsev cell nkag thiab lub hom phiaj tseem ceeb ntawm cov tshuaj tiv thaiv kab mob tsis zoo, tau siv los ua cov tshuaj tiv thaiv ib leeg los tsim cov tshuaj tiv thaiv [15,16,22] thiab Omicron's S-protein muaj 32 kev hloov pauv piv. rau hom tsiaj qus, ib nrab ntawm lawv yog nyob rau hauv RBD (Fig. 2B thiab Table 1). Muab hais tias feem ntau cov kev hloov pauv muaj me me lossis tsis cuam tshuam rau tus kab mob tus cwj pwm. Txawm li cas los xij, nyob ntawm qhov kev hloov pauv nyob rau hauv tus kab mob genome, lawv tuaj yeem cuam tshuam tus kab mob tus cwj pwm, xws li kis kab mob thiab kis kab mob. Tag nrho cov kab ke ntawm cov tsiaj qus SARS-CoV-2 S-protein muaj 1273 amino acids, 1271 hauv Delta, thiab 1270 hauv Omicron, thiab yog encoded los ntawm 3831 bps [100,101]. Ib feem ntawm S-protein raug rau cov tshuaj tiv thaiv kab mob uas cov tshuaj tiv thaiv kab mob khi hu ua epitope. Cov 1270 amino acids ua cov protein uas yog peb-dimensional (3D) hauv cov qauv, S-protein hauv Omicron, thiab muaj ntau yam epitopes ntawm nws (Fig. 2).
Los ntawm cov qauv 3D no ntawm S-protein, peb tuaj yeem xav tias tsis yog txhua qhov epitope ntawm cov protein no yuav muaj rau cov tshuaj tiv thaiv kab mob. Nws yog qhov tsim nyog xav tias qee qhov epitopes yuav quav thiab txav mus rau hauv yog li tsawg tus lej yuav raug nthuav tawm sab nraud rau cov tshuaj tiv thaiv kab mob. Feem ntau, txog rau rau cuaj cov amino acids tau ua ke los ua ib qho epitope uas tuaj yeem lees paub thiab khi los ntawm ib qho tshuaj tiv thaiv. Muab hais tias Omicron's S-protein muaj 1270 amino acids yog tias peb faib lawv los ntawm 6 uas yuav ua rau 211 epitopes linearly. Nws paub tias epitopes, tshwj xeeb tshaj yog nyob rau B hlwb thiab T hlwb, yog linear thiab conformational, tab sis lawv cov proportions tseeb tseem tsis tau paub [102]. Thaum tus kab mob lossis tshuaj tiv thaiv nkag mus rau hauv peb lub cev, lub cev tiv thaiv kab mob tsim ntau hom tshuaj tiv thaiv kab mob uas khi rau ntau yam epitopes. Cov tshuaj tiv thaiv tuaj yeem muab faib rau hauv chav kawm 1, chav kawm 2, thiab chav kawm 3, tsom mus rau qhov sib txawv me ntsis ntawm S-protein thiab tom qab ntawd ua rau SARS-CoV-2.
Piv txwv li, kev hloov pauv hu ua E484K hloov cov duab ntawm qhov chaw uas chav kawm 2 cov tshuaj tiv thaiv txheeb xyuas, ua rau lawv tsis muaj zog. Omicron harbors E484A kev hloov pauv hauv qhov chaw no thiab cov kev hloov pauv zoo sib xws hauv cov chaw rau ob chav kawm ntawm cov tshuaj tiv thaiv kab mob (Table 1). Peb caug-ob (32) bps ntawm Omicron S-protein tau hloov pauv, tsis yog txhua qhov kev hloov pauv bp yuav ua tsis tau txhua yam tshuaj tiv thaiv. Qee qhov kev hloov pauv ntsiag to, txawm tias electrochemical, electromagnetic, phenotypic, lossis cov duab hloov, tsis muaj dab tsi tshwm sim thiab tseem zoo li qub. Lub ntsiab lus yog tias peb muaj 32 bps hloov pauv ntawm 200/300 epitopes, cov 32 bps hloov pauv tuaj yeem ua txog 5-8 epitopes. Ib txhia ntawm lawv yuav sib tshooj. Tab sis hauv cov duab 3D loj, ntau qhov epitopes yuav pom. Tsis tas li ntawd, yog tias ib tus neeg muaj tus kab mob yav dhau los, lawv yuav tsis tsuas muaj cov epitopes rau S-protein, tab sis lawv kuj yuav muaj cov tshuaj tiv thaiv kab mob rau lwm cov proteins, xws li daim nyias nyias (M), lub hnab ntawv (E), nucleocapsid (N) cov proteins, thiab txawm tias cov protein tsis ua haujlwm. Muaj ntau ntau cov epitopes muaj rau lawv cov tshuaj tiv thaiv kom tau sim khi nrog. Yog li ntawd, yog tias tus kab mob no muaj qee qhov kev hloov pauv uas tsis tuaj yeem tiv thaiv kev tiv thaiv, nws yuav dim ib feem me me ntawm lub cev tiv thaiv kab mob.
Table 3 qhia tau hais tias cov tshuaj tiv thaiv kev ua tau zoo / kev ua tau zoo yog qis dua rau Omicron variant dua li Delta txhua lub sijhawm tom qab kawm thawj zaug thiab txhaj tshuaj tiv thaiv kab mob. Tshwj xeeb tshaj yog, 14–28 hnub tom qab txhaj koob tshuaj, mRNA kev ua tau zoo ntawm cov tshuaj tiv thaiv Omicron poob los ntawm 93 feem pua rau 74 feem pua, tab sis cov tshuaj tiv thaiv tseem tuaj yeem txo qhov kev pheej hmoo ntawm kev mus pw hauv tsev kho mob thiab kev tuag los ntawm Omicron-koom nrog COVID-19 [103, 104,105 ]. Hauv kev tshawb fawb tsis ntev los no, Nielsen et al. [106] muab tso ua ke cov ntaub ntawv los ntawm Danish thoob ntiaj teb cov peev txheej thiab txiav txim siab cov tshuaj tiv thaiv zoo (VE) ntawm thawj qhov tshuaj tiv thaiv COVID-19 koob tshuaj tiv thaiv SARS-CoV-2 rov kis mob, COVID-19 pw hauv tsev kho mob, thiab kev tuag. Txoj kev tshawb no tau pom tias cov tshuaj tiv thaiv tseem muaj txiaj ntsig zoo tiv thaiv SARS-CoV-2 rov kis kab mob thaum lub sijhawm nrog SARS-CoV-2 variants Alpha, Delta, thiab Omicron, xws li 71 feem pua, 94 feem pua, thiab 60 feem pua. -62 feem pua, raws li, thiab kav mus txog 9 lub hlis. Cov txiaj ntsig no zoo ib yam nrog kev tshawb fawb Qatar uas pom tias 55.1 feem pua VE tawm tsam rov kis mob nrog Omicron tom qab ob koob tshuaj tiv thaiv COVID-19 mRNA tshuaj tiv thaiv thiab 77.3 feem pua tom qab peb koob tshuaj [107,108].
Tsis tas li ntawd, ntau qhov kev tshawb fawb saib kev tiv thaiv kev tiv thaiv Omicron tau pom tias qhov nce qib ntawm cov tshuaj tiv thaiv kab mob tsis zoo vim muaj cov tshuaj tiv thaiv kab mob los yog kev sib xyaw ntawm cov kab mob ntuj tsim kom cov tshuaj tiv thaiv kab mob tsis zoo tiv thaiv Omicron hauv cov pab pawg no ntau dua lossis tsawg dua li qhov nruab nrab pom tawm tsam Delta variant hauv cov uas tau txhaj koob tshuaj tiv thaiv kab mob [53,109,110,111,112,113]. Ntxiv mus, tsis ntev los no, BNT162b2 thiab mRNA-1273 tau pom tias yuav ua rau tsis muaj Omicron thiab cov hloov pauv yav dhau los nrog cov tshuaj tiv thaiv kab mob sib kis ntau ntxiv 9-12 hnub tom qab koob thib ob [114]. Qib nruab nrab ntawm cov tshuaj tiv thaiv kab mob nruab nrab tuaj yeem tiv thaiv tib neeg los ntawm cov kab mob loj, yog li cov kws tshawb fawb ib txwm sim ntxiv cov tshuaj tiv thaiv kab mob txhawm rau txhawm rau txiav txim siab cov tshuaj tiv thaiv zoo. Txawm li cas los xij, cov tshuaj tiv thaiv kab mob muaj ntau qhov sib txawv ntawm cov neeg mob hauv tsev kho mob COVID-19 [115]. Peb paub tias feem coob ntawm cov neeg mob tuaj yeem ua tiav cov kab mob COVID{16}}, txawm tias muaj cov tshuaj tiv thaiv kab mob qis heev, thiab tau kawg, cov ntsiab lus no qhia txog lwm yam ntawm lub cev tiv thaiv kab mob, tshwj xeeb tshaj yog T cell-mediated immunity. BioNTech thiab Pfizer tau thov tias ob koob tshuaj tiv thaiv yuav tsum tseem tiv thaiv kab mob hnyav vim tias feem ntau ntawm cov qauv saum npoo ntawm Omicron S-protein tsom los ntawm T hlwb, uas feem ntau tshwm sim tom qab txhaj tshuaj, tsis cuam tshuam los ntawm kev hloov pauv hauv Omicron [116. ].
Ib txoj kev tshawb fawb bioinformatics tsis ntev los no saib ntawm Omicron's T cell epitopes tau pom tias feem ntau ntawm kev kwv yees Omicron S-protein T cell epitopes tsis hloov pauv hauv qhov hloov pauv no, qhia tias Omicron T cell tiv thaiv los ntawm kev txhaj tshuaj tiv thaiv lossis kab mob ntuj tsis cuam tshuam [117] . Ntxiv mus, ntau qhov kev tshawb fawb tsis ntev los no tau pom tias T cell tiv thaiv tseem muaj kev tiv thaiv tiv thaiv Omicron variant elicited los ntawm kev txhaj tshuaj tiv thaiv lossis kab mob ntuj [114,117,118,119,120]. Kev tshuaj ntsuam meta tsis ntev los no ntawm cov ntaub ntawv los ntawm 14,826,0342 tus neeg koom hauv 13 txoj kev tshawb fawb pom tias COVID-19 tshuaj tiv thaiv txo qis kev kis kab mob los ntawm Omicron variant [121]. Qhov zoo tshaj plaws, cov tsis muaj tshuaj tiv thaiv muaj tsib-yim-feem ntau dua ntawm kev nkag mus rau hauv tsev kho mob thiab tsib lub sij hawm ntau dua yuav kis tau tus kab mob Omicron piv rau cov uas tau txhaj tshuaj tiv thaiv feem ntau [95,122], nws yog ib qho tseem ceeb uas ua ntej. Kev tiv thaiv kab mob uas twb muaj lawm, suav nrog kev humoral, cell-mediated, thiab innate immunity, tshwm sim los ntawm cov tshuaj tiv thaiv lossis kev kis kab mob yav dhau los, tseem muaj kev tiv thaiv tiv thaiv Omicron ntsig txog COVID-19. Tau kawg, peb tsis tuaj yeem hais qhov no 100 feem pua, tab sis nws zoo li muaj kev tiv thaiv zoo heev.
6. Kev kho mob txawv txawv
Txawm hais tias cov tshuaj tiv thaiv muaj lub luag haujlwm tseem ceeb hauv kev tiv thaiv kev sib kis ntawm COVID-19 thiab txo qis kev mus pw hauv tsev kho mob thiab kev tuag, cov neeg mob uas muaj kev tiv thaiv kab mob tiv thaiv kab mob thiab cov kab mob sib kis tsis tuaj yeem tiv thaiv los ntawm kev txhaj tshuaj ib leeg. Tsis tas li ntawd, cov tshuaj tiv thaiv muaj qee qhov kev ua haujlwm sib txawv ntawm qhov sib txawv, qhia txog cov teeb meem tshiab hauv kev tiv thaiv thiab tswj Omicron thiab/lossis cov kev hloov pauv tshiab uas cuam tshuam nrog COVID-19 [123]. Yog li ntawd, nrog rau cov tshuaj tiv thaiv, nws yog ib qho tseem ceeb los txheeb xyuas cov kev kho mob uas muaj peev xwm tsom rau cov kab mob pathophysiology uas ua nws tus kheej ntawm cov noob caj noob ces ntawm SARS-CoV-2 thiab nws qhov txawv. Hauv qab no, kuv tau teev ntau cov tshuaj uas muaj zog tiv thaiv kab mob, tshuaj tua kab mob antioxidant, thiab tiv thaiv cytokine.
6.1. Remdesivir
Remdesivir yog ib qho tshuaj tiv thaiv kab mob dav dav uas tawm tsam ntau yam kab mob RNA, xws li Coronaviridae, Paramyxoviridae, thiab Filoviridae [124,125,126,127,128]. Nws yog Ameslikas tsim los tiv thaiv kab mob los ntawm Ebola thiab lwm yam kab mob [124]. Remdesivir yog ib qho tshuaj tiv thaiv ntawm adenosine analog, uas hloov mus rau cov metabolites nquag, GS-44152, nucleoside triphosphate (NTP), los ntawm tus tswv tsev [129]. NTP sib tw nrog adenosine triphosphate (ATP) rau kev koom ua ke rau hauv cov nascent RNA strand [130] (Fig. 3). Raws li ib tug nucleoside analog, redeliver shuts down viral replication los ntawm kev ua raws li ib tug 'false building block' uas yog dysfunctional thiab yog li terminates replication/transcription (Fig. 3). Hauv kev kawm hauv vitro, Wang et al. [131] qhia tias kev xa rov qab muaj txiaj ntsig zoo tiv thaiv SARS-CoV-2 kab mob hauv tib neeg lub ntsws epithelial hlwb. Raws li cov ntaub ntawv uas twb muaj lawm los ntawm kev tshawb fawb hauv vitro [131], ntau qhov chaw ntau qhov kev sim tshuaj ntsuam xyuas (RCTs) ntawm remdesivir ntawm cov neeg laus hauv tsev kho mob COVID-19 cov neeg mob tau ua tiav [132,133]. RCTs yog tus qauv kub rau kev soj ntsuam ntawm qhov muaj peev xwm kho tau zoo. Ib qho RCT ntawm remdesivir tau qhia tias ob qho tib si 10-hnub chav kawm thiab chav kawm 5- hnub ua kom lub sijhawm rov qab los ntawm cov neeg mob hauv tsev kho mob nrog COVID-19 [133].
Lwm ob qhov muag tsis pom kev, RCT ntawm 3-hnub chav kawm ntawm remdesivir tau txais kev nyab xeeb profile thiab ua rau 87 feem pua kev pheej hmoo ntawm kev mus pw hauv tsev kho mob lossis kev tuag tsawg dua li cov placebo hauv 7 hnub ntawm cov tsos mob [134]. Raws li cov ntaub ntawv los ntawm RCTs, Remdesivir (VeklurR) tau txais kev pom zoo los ntawm US FDA thawj zaug ua thawj cov tshuaj tiv thaiv kab mob rau kev kho mob me me mus rau nruab nrab COVID-19 cov tsos mob cov neeg mob thiab yog cov neeg muaj kev pheej hmoo siab. rau kev nce mus rau qhov mob hnyav COVID-19, suav nrog kev mus pw hauv tsev kho mob lossis tuag uas muaj hnub nyoog 12 xyoos lossis laus dua [135]. Tab sis cov tshuaj yuav tsum tau txhaj tshuaj intravenously, uas txwv tsis pub nws cov nqi hluav taws xob, tshwj xeeb tshaj yog nyob rau hauv cov cheeb tsam uas cov chaw kho mob infusion yuav tsis yooj yim. Tsis tas li ntawd, kev sib koom ua ke sim ua los ntawm World Health Organization (WHO) tsis pom qhov txiaj ntsig zoo li no [136]. Cov no hais txog qhov yuav tsum tau nrhiav cov tshuaj tiv thaiv kab mob tshiab.
6.2. Molnupiravir
Molnupiravir yog ib qho tshuaj tiv thaiv kab mob uas tsis ntev los no tau raug pov thawj hauv randomized-placebo tswj kev sim tshuaj rau kev kho mob ntawm COVID-19 cov neeg mob [137]). Molnupiravir yog ib qho nucleoside analog uas nce qhov zaus ntawm tus kab mob RNA hloov pauv los ntawm RNA-dependent RNA-polymerase (RdRp) thiab nws inhibits ntau yam kab mob sib kis nrog rau SARS-CoV-2 hauv cov qauv tsiaj thiab tib neeg [138,139,140, 141,142, Thaum Molnupiravir nkag mus rau hauv lub cell, nws hloov mus rau nws daim ntawv nquag, -dN4 -deoxycytidine triphosphate (M). M tuaj yeem siv los ntawm SARS-CoV-2 tus kab mob RdRp, ua substrate es tsis txhob cytidine triphosphate lossis uridine triphosphate. RdRp yog ib qho tseem ceeb heev enzyme rau SARS-CoV{19}} virus replication. M-muaj RNA tuaj yeem siv los ua tus qauv tom qab ntawd ua rau cov khoom lag luam hloov pauv RNA, uas tsis txhawb kev rov ua dua ntawm cov kab mob tshiab tsis zoo (Daim duab 3) [140], raws li kev kwv yees los ntawm 'yuam kev puas tsuaj' qauv [138, 144,145] . Txij li thaum lub mechanism ntawm kev txiav txim ntawm Molnupiravir yog ywj siab ntawm kev hloov nyob rau hauv lub spike protein, nws yuav tsum ua hauj lwm tiv thaiv Omicron.
Tseeb tiag, Molnupiravir muaj cov txiaj ntsig zoo sib xws rau Alpha, Beta, Gamma, Delta, thiab Omicron hauv vitro kev tshawb fawb ntawm VeroE{{0}}GFP hlwb txawm tias tsis muaj kev tshawb fawb soj ntsuam los qhia txog kev ua tau zoo ntawm Molnupiravir hauv cov neeg mob. nrog Omicron [146]. Ib qhov ob-dig muag RCT tau ua rau cov neeg laus uas tsis nyob hauv tsev kho mob nrog 800 mg ntawm qhov ncauj covid-19 tshuaj txhua hnub rau 5- hnub ua ntej Omicron nthwv dej (Tsib Hlis 2021 txog Kaum Ib Hlis 2021). Hauv kev tshuaj xyuas ntawm 1433 tus neeg koom, feem pua ntawm cov neeg koom nrog hauv tsev kho mob lossis tuag txog hnub 29 tau qis dua: 6.8 feem pua (48 ntawm 709) hauv pab pawg cuam tshuam piv nrog 9.7 feem pua (68 ntawm 699) hauv pawg placebo (RR, − 3.1% ; 95% CI, − 5.9 to − 0.1) [137] (Table 4). Hauv lwm txoj kev tshawb fawb, Molnupiravir tau pom tias txo qis kev pheej hmoo ntawm kev mus pw hauv tsev kho mob lossis kev tuag los ntawm 50 feem pua ntawm cov neeg laus tsis nyob hauv tsev kho mob [147]. Raws li cov ntaub ntawv, Molnupiravir tau tso cai los ntawm FDA rau kev siv thaum muaj xwm txheej ceev rau kev kho mob me me mus rau nruab nrab COVID-19 hauv cov neeg laus nrog cov txiaj ntsig zoo ntawm kev kuaj SARS-CoV-2 ncaj qha uas muaj kev pheej hmoo siab. rau kev nce mus rau qhov mob hnyav COVID-19 suav nrog kev mus pw hauv tsev kho mob thiab kev tuag.
6.3. Paxlovid ™
Paxlovid™ yog ib qho khoom ua ke uas muaj nirmatrelvir [PF-07321332] thiab ritonavir. Nirmatrelvir yog SARS-CoV-2 lub ntsiab protease inhibitor (Mpro, 3CLpro, los yog nsp5 protease inhibitor), yog ib qho tseem ceeb enzyme uas cov kab mob yuav tsum tau sib npaug hauv tib neeg lub cev [148]. Inhibition of SARS-CoV-2 Mpro renders the virus incapable of processing polyprotein precursors, li no tiv thaiv kab mob replication (Fig. 3). Luv luv thaum tus kab mob txuas mus rau lub hlwb los ntawm ACE2 receptors, nws tso nws tus kab mob RNA mus rau hauv lub cell cytoplasm. Ribosomes hauv RNA tsim cov chains polyprotein. Cov kab protein ntev yog cleaved los ntawm enzymes hu ua proteases rau hauv cov kab mob me me. Cov kab mob kis kab mob tsim ib qho nyuaj uas tom qab ntawd ua rau RNA replication, thaum kawg, sib dhos thiab tso tawm tus kab mob tshiab tshwm sim los ua kom tiav cov txheej txheem. Txij li thaum nirmatrelvir muaj nyob rau hauv Paxlovid ™ thaiv lub ntsiab protease, 3CL, thiab tiv thaiv kev tawg ntawm polyprotein rau hauv me me.
Qhov no thaum kawg tiv thaiv RNA replication thiab nres ntxiv cov kab mob ntau lawm. Ritonavir yog CYP3A inhibitor suav nrog kom nce nirmatrelvir plasma concentrations. Cov koob tshuaj ntau dua ntawm ritonavir siv los ua tus kab mob HIV protease inhibitor [149]. Kev tshawb fawb hauv vitro tsis ntev los no qhia tias Mpro mutants ntawm SARS-CoV-2 variants tseem raug rau nirmatrelvir. Lawv tau txheeb xyuas cov kab mob Mpro uas muaj ntau tshaj plaws suav nrog G15S, T21I, L89F, K90R, P132H, thiab L205V hauv cov kab mob sib txawv ntawm SARS-CoV-2 kab mob suav nrog Beta, Lambda, thiab Omicron, thiab kev soj ntsuam biochemical pom tias nirmatrelvir tau cog lus muaj zog tiv thaiv txhua qhov sib txawv, qhia tias Paxlovid ™ tuaj yeem ua tau zoo tiv thaiv Omicron variant [150]. Hauv ob qhov muag tsis pom kev, cov placebo-tswj theem II / III kev sim ua los ntawm Pfizer Inc. Paxlovid™ tau pom tias txo qis kev mus pw hauv tsev kho mob thiab kev tuag los ntawm 89 feem pua thaum noj hauv 3 hnub ntawm cov tsos mob tshwm sim (Table 4). Qhov tseem ceeb, qhov kev tuag tau pom tias txo qis nrog qhov tseem ceeb (p <0.0001) [151,152]. Kev tshuaj ntsuam meta tsis ntev los no ntawm 18,568 tus neeg mob cov ntaub ntawv los ntawm 41 RCTs piv qhov ua tau zoo ntawm cov tshuaj tiv thaiv kab mob hauv cov neeg mob COVID-19 pom tias malnupiravir thiab simeprevir-ritonavir (Paxovid™) txo qis kev pheej hmoo ntawm kev mus pw hauv tsev kho mob thiab tuag. Paxlovid ™ muaj txiaj ntsig zoo dua li malnupiravir hauv kev txo qis kev pheej hmoo ntawm kev mus pw hauv tsev kho mob [153]. Cov kev tshawb pom no ua rau muaj kev cia siab tshiab tias Paxlovid™ yog txoj kev kho mob zoo rau cov neeg mob COVID{29}}. Ntxiv mus, ntau qhov kev sim tshuaj ntawm Paxlovid ™ tam sim no tab tom ua thiab yuav nthuav tawm sai sai [154, 155,156,157].
Raws li qhov muaj peev xwm ua tau zoo tiv thaiv COVID-19, FDA tau muab kev tso cai siv thaum muaj xwm ceev rau Pfizer cov tshuaj tiv thaiv kab mob, Paxlovid™ thaum Lub Kaum Ob Hlis 2021 rau kev kho mob me me rau nruab nrab COVID-19 hauv cov neeg laus thiab cov neeg mob me. (12 xyoos thiab laus dua). Nws yog tsim los qhia ntxov tom qab kuaj pom tsis pub dhau 5 hnub ntawm cov tsos mob uas muaj kev pheej hmoo siab rau kev loj hlob mus rau COVID-19, suav nrog tsev kho mob lossis tuag. Nirmatrelvir tau raug pom tias muaj kev nyab xeeb thiab ua tau zoo yam tsis muaj kev phiv ntawm qhov ncauj noj txog 600 mg / kg ib hnub hauv cov liab thiab 1000 mg / kg txhua hnub hauv nas rau 14 hnub [158]. Paxlovid™ yog thawj cov tshuaj tiv thaiv kab mob hauv qhov ncauj hauv tsev kho mob rau COVID-19 thiab suav tias yog 'game changer' tshuaj vim nws tsis tas yuav tsum tau txhaj tshuaj intravenously xws li remdesivir.
6.4. Fluvoxamine
Fluvoxamine yog ib qho tshuaj uas tau pom zoo los ntawm FDA rau qee yam kev puas siab puas ntsws, xws li kev nyuaj siab loj, kev cuam tshuam rau lub caij nyoog, kev xav tsis zoo, thiab kev ntxhov siab tom qab kev nyuaj siab tab sis kuj zoo li yog ib feem uas nws ua haujlwm hauv kev txo qis oxidative kev nyuaj siab thiab mob. thiab txawm tias cytokine cua daj cua dub uas cuam tshuam tsawg kawg hauv qee qhov kev mus pw hauv tsev kho mob cuam tshuam nrog COVID-19. Lub luag haujlwm tseem ceeb ntawm fluvoxamine yog lub npe hu ua kev xaiv serotonin reuptake inhibitor (SSRI) uas ua rau muaj txiaj ntsig zoo ntawm serotonin hauv cov synaptic cleft lossis cheeb tsam, ua rau muaj kev nce ntxiv ntawm cov serotonin receptors thiab thaum kawg, ua rau muaj kev zoo siab ntawm tus ncej. -synaptic receptor thiab thaum kawg nyem cov teeb meem saum toj no [159]. Cov txheej txheem ntawm kev ua ntawm fluvoxamine hauv COVID-19 tseem tsis tau paub, tab sis nws muaj zog antioxidant thiab tiv thaiv cytokine cov haujlwm uas yuav muaj txiaj ntsig zoo rau kev txhim kho COVID-19 cov txiaj ntsig (Fig. 4). Cov ntaub ntawv pov thawj qhia tau tias tus kab mob SARS-CoV-2 ua rau oxidative stress nyob rau hauv lub hlwb.
Tsis tas li ntawd, COVID-19 cov neeg mob rog rog, ntshav qab zib mellitus, kab mob plawv, kev laus, thiab kev tiv thaiv kab mob ua rau pom cov qib siab ntawm cov pa oxygen reactive (ROS) thiab oxidative stress [160]. Lub inositol reuptake enzyme ib alpha (IRE1), mitochondrial membrane protein tuaj yeem paub qhov nce qib ntawm ROS hauv cell, thiab los ntawm ntau cov txheej txheem nyuaj, qhov tseem ceeb, IRE1 activates nuclear factor kappa beta (NF-κB) uas nkag mus rau hauv lub nucleus. thiab ua rau transcription ntawm DNA los ua inflammatory yam xws li cytokines, xws li nyob rau hauv cytokine cua daj cua dub [161,162]. Kev ntxhov siab oxidative ua ke nrog cua daj cua dub cytokine yog ib qho kev paub txog qhov mob hnyav ntawm COVID-19 [160]. Dhau li ntawm kev ua SSRI, fluvoxamine txhawb nqa sigma 1 receptor (SIR), mitochondrial daim nyias nyias uas ua ke nrog IRE1 thiab qhov tseem ceeb txias nws thiab tiv thaiv nws los ntawm kev ua ntau yam ntawm nws cov haujlwm xws li txhawb nqa NF-κB uas ua rau txo qis hauv cytokine. cua daj cua dub [161,163]. Lwm cov tswv yim pom zoo tuaj yeem pab txhawb kev tiv thaiv COVID-19 suav nrog txo qis hauv platelet aggregation, inhibition ntawm histamine tso tawm los ntawm mast hlwb, thiab cuam tshuam nrog endolysosomal viral trafficking [164,165].
Rau qhov muaj txiaj ntsig zoo li no, cov kws tshawb fawb tau tsim ib qho RCT los saib seb puas yog fluvoxamine puas yuav txhim kho cov txiaj ntsig hauv COVID{{{{20}}}}, thiab cov txiaj ntsig tau tshaj tawm thaum lub Kaum Ib Hlis 2020 [166]. Hauv qhov no RCT (n=152), fluvoxamine tau pom los tiv thaiv kev kho mob tsis zoo hauv cov neeg laus laus uas muaj tus mob SARS-CoV-2. Tom qab ntawd, cov txiaj ntsig zoo sib xws tau pom nyob rau hauv qhov kev cia siab, uas tsis yog-randomized observational cohort kev tshawb fawb thiab meta-analysis ntawm fluvoxamine nyob rau hauv cov neeg mob sab nraud (n=113) kis nrog SARS-CoV-2 [167,168]. Txij li cov qauv loj me me, cov kev tshawb fawb no tau txhawb nqa ntxiv ob-dig muag RCTs siv tus qauv loj. Tom qab ntawd, cov qauv loj loj (n=1480) ob-dig muag RCT pom tau tias kev kho mob fluvoxamine ntawm koob tshuaj 100 mg rau 10 hnub txo qis kev mus pw hauv tsev kho mob lossis tuag los ntawm 29 feem pua (95 feem pua CI 0.54–0.93) hauv high- muaj kev pheej hmoo rau cov neeg mob sab nraud piv rau pawg placebo (Table 4) [169]. Lawv kuj tau piv peb lub tebchaw, fluvoxamine, metformin, thiab ivermectin. Metformin thiab ivermectin tsis pom muaj txiaj ntsig zoo. Fluvoxamine tej zaum yuav yog tus neeg siv tshuaj txaus nyiam tshaj plaws rau theem pib ntawm COVID-19. Nws muaj kev ruaj ntseg profiles, muaj dav dav, thiab yog pheej yig heev rau kev hais lus thiab kuj siv tau rau cov menyuam yaus thiab cov tub ntxhais hluas [170]. Kev tshuaj ntsuam meta tsis ntev los no ntawm 4842 tus neeg koom hauv yim txoj kev tshawb fawb ua ke Fluvoxamine nrog Paxlovid™ lossis Malnupiravir tau pom tias cov tshuaj tshiab no tau ua haujlwm zoo hauv kev txo qis kev tuag thiab kev mus pw hauv tsev kho mob hauv Omicron-koom nrog COVID-19 cov neeg mob [171].
6.5. Tempol
Tsis ntev los no, Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv Hauv Tebchaws (NIH) tau hais txog Tempol tias yog tus kws kho mob muaj peev xwm rau kev kho mob COVID-19. Cov tshuaj tiv thaiv kab mob siab tiv thaiv kab mob tshwm sim los ntawm cytokine cua daj cua dub ua ke nrog oxidative kev nyuaj siab ua rau COVID-19 pathogenesis uas yog tus cwj pwm los ntawm endothelial cell dysfunction thiab enodtheliitis uas ua rau thrombosis uas tuaj yeem ua rau lub ntsws thiab lwm yam kabmob tseem ceeb uas ua rau lub plawv. nres thiab mob stroke thiab thaum kawg yuav ua rau tuag [160]. Tempol tau lees tias muaj "Peb nyob rau hauv ib qho", xws li tshuaj tiv thaiv kab mob, tshuaj tua kab mob, thiab tshuaj tua kab mob antioxidant, muaj cov haujlwm zoo li no tau ua rau muaj kev cia siab tshiab tias Tempol yuav yog txoj kev kho mob zoo rau cov neeg mob COVID-19. Raws li kev ua ub no, Adamis Pharmaceuticals tau xa daim ntawv thov nrhiav kev ceev nrawm los ntawm FDA rau Tempol ua cov tshuaj muaj peev xwm rau COVID-19 kev tswj hwm hauv tsev.
Tempol yog redox-cycling nitroxide uas txhawb cov metabolism ntawm ROS thiab txhim kho nitric oxide (NO) bioavailability [172,173]. Txawm li cas los xij, qhov txo qis bioavailability ntawm NO ua rau endothelial cell dysfunction [174], uas ua rau kev tso tawm ntawm coagulation yam uas ua rau thrombosis [160,175]. Tempol muaj superoxide dismutase (SOD) mimetic kev ua si uas catalyzes dismutation ntawm superoxide (O2 −) rau O2 thiab H2O2. Preclinical kev tshawb fawb ntawm Tempol tau pom tias txo qis ischemia / reperfusion-induced kab mob los ntawm nws cov dawb radical scavenging kev ua [176,177,178]. Tsis tas li ntawd, Tempol tau pom tias txo qis oxidative kev nyuaj siab los ntawm kev ua kom lub cev muaj zog erythroid 2-txog yam 2 (Nrf2) txoj hauv kev. Tempol tau pom tias yuav txo qis cov cytokines, txawm tias cytokine cua daj cua dub los ntawm kev tsis ua haujlwm ntawm NF-κB txoj hauv kev [179]. Cov kev tshawb fawb ua ntej ntawm Tempol tau pom tias txo qis cytokines los ntawm ntau hom cell [172,179].
Tsis ntev los no, cov tshuaj tiv thaiv cytokine cuam tshuam ntawm Tempol tau tshawb xyuas ntawm COVID-19 cov neeg mob. Cov kws sau ntawv pom qhov txo qis hauv ntau T cell thiab APC-los ntawm cytokines los ntawm cov hlwb ntawm COVID-19 hauv vitro [180]. Ntxiv mus, Tempol tau pom tias yuav txo tau cov kab mob COVID-19 los ntawm inhibiting RdRp thiab thaiv cov SARS-CoV-2 viral replication in vitro [181]. Daim ntawv tshaj tawm dhau los tau qhia tias Tempol ncaj qha cuam tshuam nrog cov hlau-sulfur (Fe-S) pawg thiab nws muaj peev xwm oxidize thiab disassemble Fe-S pawg [182]. Fe-S pawg tam sim no nyob rau hauv catalytic subunit ntawm RdRp yog qhov tseem ceeb rau SARS-CoV-2 replication thiab kis. Hauv tsab ntawv ceeb toom tsis ntev los no, Maio et al. qhia tias Tempol thiab remdesivir synergistically inhibit qhov kev ua ntawm RdRp thiab thaiv SARS-CoV{14}} replication [181].
Zuag qhia tag nrho, txawm hais tias feem ntau ntawm cov kev tshawb fawb yog preclinical siv cov qauv tsiaj thiab cov kab lis kev cai ntawm tes, nws xav tias Tempol tuaj yeem cuam tshuam cytokines ntau lawm thiab tiv thaiv kab mob los ntawm kev ua kom mob, txo qis oxidative kev nyuaj siab, thiab clumping ntawm platelets [172,179, 180,181,183]. Ntau RCTs yuav tsum tau ceev nrooj los piav qhia lub luag haujlwm ntawm Tempol hauv kev txo tus kab mob SARS-CoV-2. A Theem 2/3, yoog raws, RCT tau pib tshuaj xyuas qhov cuam tshuam ntawm Tempol hauv kev tiv thaiv COVID-19 mus pw hauv tsev kho mob hauv cov neeg mob uas muaj tus kab mob SARS-CoV-2 (Table 4) [184]. Txawm hais tias cov txiaj ntsig ntawm txoj kev tshawb no yuav nkag mus tau sai sai thiab yuav muab cov ntaub ntawv tseem ceeb ntawm Tempol pab rau cov neeg mob COVID-19 li cas, cov tshuaj tua kab mob muaj zog, tiv thaiv cytokine, thiab cov tshuaj tiv thaiv antioxidant tej zaum yuav muaj txiaj ntsig zoo thaum ntxov thiab hnyav. SARS-CoV-2 infection.
6.6. Vitamin D
Vitamin D yog cov rog-soluble uas yog endogenously synthesized nyob rau hauv peb lub cev los ntawm tshav ntuj raug thiab kuj yuav tau txais los ntawm supplementation. Nws paub tias qib ntshav ntawm 30 ng / mL ntawm vitamin D yog qhov tseem ceeb rau kev txhawb nqa kev tiv thaiv kab mob [185], thaum qis dua 20 ng / mL yog suav tias yog vitamin D tsis txaus, thiab qib ntawm 21 thiab 29 ng / mL yog suav tias yog tsis txaus [186] . Zuag qhia tag nrho, kev tsim cov kab mob hauv ib tus neeg, suav nrog COVID-19, feem ntau nyob ntawm kev tiv thaiv tus tswv tsev, xws li kev tiv thaiv kab mob hauv lub cev thiab hloov pauv, yog li kev txhawb nqa kev tiv thaiv yog ib lub tswv yim tseem ceeb heev los tiv thaiv kab mob. Vitamin D boosts lub cev tsis muaj zog tiv thaiv kab mob uas txo cov kab mob kis thiab txo cov kev ua dhau los ntawm kev hloov kho lub cev tiv thaiv kab mob thiab cytokine cua daj cua dub, yog li txo tus kab mob COVID-19 kev tuag [187]. Muaj ntau cov pov thawj tias vitamin D yog ib tug muaj zog kho mob tus neeg sawv cev tiv thaiv SARS-CoV{12}} kab mob (Table 4) [187,188,189,190]. Tsis tas li ntawd, kev sib xyaw ua ke ntawm cov vitamin D thiab L-cysteine, COVID-19, muaj txiaj ntsig zoo dua los txo cov kev pheej hmoo ntawm oxidative kev nyuaj siab thiab cytokine cua daj cua dub thaum kis kab mob [191]. Magnesium deficiency kuj tau txuas rau txo lub cev tiv thaiv kab mob thiab ua rau muaj mob ntxiv [192], thiab ntxiv nrog cov vitamin D tau pom tias ua kom muaj kev tiv thaiv kab mob [193]. Tsis tas li ntawd, cov vitamin D ua ke nrog cov tshuaj NAC muaj peev xwm txo tau oxidative kev nyuaj siab nrog rau kev txhawb nqa kev tiv thaiv kab mob SARS-CoV-2 [191].
6.7. Vitamin C
Vitamin C yog cov dej-soluble tseem ceeb vitamin, qhov tsis muaj peev xwm ua rau oxidative kev nyuaj siab thiab mob, thiab txo kev tiv thaiv. Nws tau raug tshaj tawm tias qib plasma ib txwm yog 50 μmol / L [194], nrog hypovitaminosis qis dua ~ 23 μmol / L thiab qhov tsis txaus qis dua 11 μmol / L [195]. Yog li, cov neeg mob uas muaj vitamin C tsis txaus yuav, feem ntau, yuav muaj kev pheej hmoo siab dua rau COVID-19 thiab yog li tau txais txiaj ntsig los ntawm kev noj cov vitamin C. Kev soj ntsuam soj ntsuam ntawm 21 tus neeg mob hnyav COVID-19 cov neeg mob tau mus rau ICU pom tias cov neeg muaj sia nyob 11 cov neeg mob muaj ntshav plasma ntawm 29 μmol / L ntawm vitamin C thaum cov neeg tsis muaj sia nyob muaj 15 μmol / L [196]. Kev sim tshuaj ntsuam xyuas tsis ntev los no ntawm vitamin C tau pom tias muaj txiaj ntsig zoo rau cov neeg mob hnyav nrog COVID{14}} los ntawm kev txhim kho oxygenation [197]. Vitamin C tau pom los ua kom cov IFNs ntau lawm uas txhim kho cov tshuaj tiv thaiv kab mob [198,199]. Tsis tas li ntawd, vitamin C tau pom tias yuav txo tau qhov mob, txawm tias cytokine cua daj cua dub, los ntawm inactivating NF-κB txoj kev [200]. Nws tseem tuaj yeem txo qhov tsim ntawm neutrophil extracellular trap (NET) uas cuam tshuam nrog vascular puas thiab ntshav txhaws [201]. Tsis tas li ntawd, nws txo qis oxidative kev nyuaj siab uas ua rau muaj kev txhim kho endothelial kev ncaj ncees thiab kho qhov txhab, uas tej zaum yuav yog ib lub tswv yim muaj txiaj ntsig zoo rau cov kab mob SARS-CoV-2 thaum ntxov thiab hnyav [202,203,204].
7. Cov lus xaus
Cov pov thawj loj hlob qhia tau hais tias qib ntawm cov tshuaj tiv thaiv kab mob tsis zoo tiv thaiv kab mob Omicron tau txo qis piv rau cov poj koob yawm txwv kab mob SARS-CoV-2 ntawm cov neeg tau txais cov tshuaj tiv thaiv thawj zaug lossis cov uas yav dhau los kis tus kab mob SARS-CoV-2. Txawm li cas los xij, qhov nruab nrab cov tshuaj tiv thaiv kab mob tseem tshuav ntau dua 55 feem pua tom qab txhaj tshuaj tiv thaiv thawj zaug thiab txhim kho nrog cov tshuaj tiv thaiv kom siab dua 74 feem pua. Nyob rau hauv qhov sib piv rau qhov kev tshawb pom ntawm kev tiv thaiv kab mob humoral, ntau cov ntaub ntawv ntawm kev tiv thaiv kab mob ntawm tes tau txiav txim siab tias 70-80 feem pua ntawm CD4 ntxiv thiab CD8 ntxiv cov lus teb tau khaws cia rau tus kab mob Omicron, cov neeg uas tau kis tus kab mob yav dhau los, thiab / lossis tau txhaj tshuaj tiv thaiv yav dhau los. T cell tiv thaiv zoo rau Omicron tuaj yeem pab tiv thaiv kab mob hnyav, thiab tuaj yeem txo qhov kev pheej hmoo ntawm kev mus pw hauv tsev kho mob thiab txawm tias tuag. Hauv qhov tseeb, vim qhov tshwm sim ntawm qhov sib txawv ntawm SARS-CoV-2, cov tshuaj tiv thaiv ib leeg tsis tuaj yeem muab kev tiv thaiv 100 feem pua ntawm kev sib kis. Ntxiv nrog rau qhov sib txawv ntawm kev vam khom, cov tib neeg muaj kev tiv thaiv kab mob tau txo qis kev siv tshuaj tiv thaiv, txawm tias tom qab koob tshuaj ntxiv. Cov kev pabcuam khomob tsom rau kev ntxhov siab oxidative, cua daj cua dub cytokine, thiab cov kab mob sib kis tau xav tias yuav muaj txiaj ntsig zoo hauv kev tswj hwm cov neeg mob hnyav lossis tseem ceeb ntawm COVID{14}}.
Kev soj ntsuam tsis ntev los no, preclinical, thiab RCTs qhia tias Paxlovid™, Molnupiravir, Fluvoxamine, thiab Tempol tau khaws cov tshuaj tua kab mob antioxidants, tshuaj tiv thaiv cytokine, thiab tshuaj tiv thaiv kab mob tiv thaiv Omicron-associated COVID-19. Qhov tseem ceeb, kev ceev faj txog kev noj qab haus huv rau pej xeem uas twb muaj lawm xws li hnav lub qhov ncauj qhov ntswg, zam qhov chaw nyob ze, tswj lub cev nyob deb, thiab kev huv ntawm tes uas muaj txiaj ntsig zoo rau cov kev hloov pauv yav dhau los yuav tsum muaj txiaj ntsig zoo rau Omicron variant. Ntxiv rau qhov no, peb pom zoo kom tau txais tsawg kawg 8 teev ntawm kev pw tsaug zog txhua hmo, zam kev ntxhov siab thiab qaug zog, qoj ib ce kom txaus, raug tshav ntuj txaus, nrog rau kev noj cov micronutrients, suav nrog cov vitamins (vitamin D thiab vitamin C) thiab cov zaub mov (magnesium, zinc, selenium) uas txhim kho kev tiv thaiv tag nrho thiab yuav muaj txiaj ntsig zoo hauv kev tiv thaiv kab mob Omicron. Sib sau ua ke, qhov kev nkag siab tam sim no taw qhia txog qhov muaj peev xwm tshawb nrhiav qhov tsis sib xws thiab yuav pab txhim kho cov kab mob tshiab tshiab COVID-19 cov tshuaj tiv thaiv thiab tshuaj tiv thaiv kab mob los tiv thaiv Omicron, nws cov sublineages, lossis cov kev hloov tshiab tshiab ntawm SARS-CoV-2 .
Tus sau phau ntawv pab nyiaj
MS Alam yog tus sau tsab xov xwm.
Daim ntawv qhia nyiaj txiag
Qhov kev tshawb fawb no tsis tau txais ib qho nyiaj pab tshwj xeeb los ntawm cov koom haum pab nyiaj hauv pej xeem, kev lag luam, lossis tsis tau txais txiaj ntsig.
Cov ntaub ntawv muaj nyob
Cov ntaub ntawv suav nrog hauv kab lus / supp. cov ntaub ntawv / siv nyob rau hauv tsab xov xwm.
Tshaj tawm ntawm Kev Tshaj Lij Tshaj Lij Tshaj Tawm
Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.
Cov ntaub ntawv
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