Ntau cov tshuaj tiv thaiv twb tau siv los yog tab tom txhim kho raws li kev kho mob rau kev kho tus kab mob COVID-19.Nrog rau qhov tshwm sim ntawm qhov hloov pauv tshiab ntawm tus mob hnyav ua pa nyuaj rau tus mob coronavirus 2 (SARS-CoV-2), nws yog ib qho tseem ceeb rau kev kwv yees seb lawv puas tseem yuav raug tshuaj tiv thaiv kab mob.Starr et al.Ib lub tsev qiv ntawv poov xab tau siv, uas suav nrog txhua qhov kev hloov pauv hauv SARS-CoV-2 receptor binding domain uas yuav tsis cuam tshuam rau kev khi rau tus tswv tsev receptor (ACE2), thiab qhia seb qhov kev hloov pauv no cuam tshuam li cas rau peb lub ntsiab tiv thaiv SARS-CoV. -2 antibody khi.Cov duab no qhia txog kev hloov pauv uas khiav tawm cov tshuaj tiv thaiv kab mob, suav nrog kev hloov pauv ib leeg uas khiav tawm ob cov tshuaj tiv thaiv kab mob hauv Regeneron antibody mix.Ntau qhov kev hloov pauv uas khiav tawm ib qho tshuaj tiv thaiv kab mob kis tau rau tib neeg.
Cov tshuaj tiv thaiv kab mob yog ib qho kev kho mob uas muaj peev xwm kho tau tus mob hnyav ua pa nyuaj rau tus mob coronavirus 2 (SARS-CoV-2), tab sis nws tsis paub meej tias tus kab mob no txhim kho kom dim lawv txoj kev pheej hmoo.Ntawm no, peb daim ntawv qhia yuav ua li cas tag nrho cov kev hloov pauv hauv SARS-CoV-2 receptor binding domain (RBD) cuam tshuam rau kev khi ntawm REGN-COV2 cocktail rau cov tshuaj tiv thaiv LY-CoV016.Cov ntawv qhia ua tiav no tau nthuav tawm qhov kev hloov pauv ntawm cov amino acid uas ua tiav tag nrho cov REGN-COV2 sib tov, uas yog tsim los ntawm ob lub tshuaj tiv thaiv REGN10933 thiab REGN10987 uas lub hom phiaj sib txawv ntawm cov txheej txheem epitopes.Cov nuj nqis no tseem txheeb xyuas cov kab mob hloov pauv uas tau xaiv hauv cov neeg mob tsis tu ncua uas tau kho nrog REGN-COV2 thiab thaum nyob hauv vitro tus kab mob khiav dim.Thaum kawg, cov duab no qhia tau tias kev hloov pauv uas khiav tawm ib qho tshuaj tiv thaiv kab mob twb muaj nyob rau hauv cov kab mob SARS-CoV-2.Daim ntawv qhia kev khiav tawm no tuaj yeem piav qhia txog qhov tshwm sim ntawm kev hloov pauv tau pom thaum lub sijhawm soj ntsuam tus kab mob.
Cov tshuaj tiv thaiv tau raug tsim los kho mob hnyav ua pa nyuaj ua pa mob coronavirus 2 (SARS-CoV-2) (1).Cov tshuaj tiv thaiv kab mob tiv thaiv qee yam kab mob tuaj yeem ua rau tsis muaj txiaj ntsig los ntawm kev hloov pauv ntawm tus kab mob xaiv thaum kho cov neeg mob muaj kab mob (2, 3) lossis cov kab mob sib kis uas tau kis thoob ntiaj teb kom lees paub tiv thaiv tag nrho cov kab mob.Yog li ntawd, kev txiav txim siab uas SARS-CoV-2 kev hloov pauv tuaj yeem khiav tawm cov tshuaj tiv thaiv kab mob tseem ceeb yog qhov tseem ceeb los ntsuas seb qhov kev hloov pauv tau pom thaum lub sijhawm soj ntsuam tus kab mob cuam tshuam li cas ntawm kev kho tshuaj tiv thaiv kab mob.
Feem ntau cov thawj coj los tiv thaiv SARS-CoV-2 cov tshuaj tiv thaiv lub hom phiaj ntawm tus kab mob receptor binding domain (RBD), uas kho kom haum rau cov angiotensin converting enzyme 2 (ACE2) receptor (5, 6).Tsis ntev los no, peb tau tsim ib txoj hauv kev sib sib zog nqus scanning los qhia seb txhua qhov kev hloov pauv ntawm RBD cuam tshuam rau nws txoj haujlwm thiab kev lees paub los ntawm cov tshuaj tiv thaiv kab mob (7, 8).Cov txheej txheem suav nrog kev tsim cov tsev qiv ntawv ntawm RBD mutants, qhia lawv nyob rau saum npoo ntawm cov poov xab, thiab siv fluorescence-activated cell sorting thiab sib sib zog nqus sequencing kom paub meej tias txhua qhov kev hloov pauv cuam tshuam li cas rau RBD folding, ACE2 affinity ( ntsuas hauv titration series), thiab antibody binding. (Daim duab S1A).Nyob rau hauv txoj kev tshawb no, peb siv lub repetitive mutant tsev qiv ntawv piav nyob rau hauv (7), uas yog tsim los ntawm barcoded RBD variants, npog 3804 ntawm 3819 muaj peev xwm amino acid mutations.Peb lub tsev qiv ntawv tau npaj los ntawm RBD keeb kwm keeb kwm ntawm kev cais tawm thaum ntxov Wuhan-Hu-1.Txawm hais tias qhov zaus ntawm ntau tus mutants nce, lawv tseem sawv cev rau feem ntau RBD sequences (9, 10).Peb tau kos ob qho kev hloov pauv ntawm 2034 uas tsis cuam tshuam rau RBD folding thiab ACE khi (7) yuav ua li cas dhau REGN-COV2 cocktail (REGN10933 thiab REGN10987) (11, 12) thiab Eli Lilly's LY-CoV016 Daim ntawv rov ua dua ntawm cov cov tshuaj tiv thaiv kab mob cuam tshuam rau txoj kev khi cov tshuaj tiv thaiv kab mob (tseem hu ua CB6 lossis JS016) (13) (Daim duab S1B).REGN-COV2 tsis ntev los no tau tso cai siv thaum muaj xwm txheej ceev rau COVID-19 (14), thaum LY-CoV016 tam sim no tab tom ua rau theem 3 kev sim tshuaj (15).
[Glu406 → Trp(E406W)] muaj zog khiav tawm ntawm ob lub tshuaj tiv thaiv kab mob (Daim duab 1A).Daim ntawv qhia kev khiav tawm ntawm LY-CoV016 kuj tau nthuav tawm ntau qhov kev hloov pauv ntawm cov chaw sib txawv hauv RBD (Daim duab 1B).Txawm hais tias qee qhov kev hloov pauv hloov pauv tuaj yeem cuam tshuam lub peev xwm ntawm RBD los khi rau ACE2 lossis nthuav tawm hauv daim ntawv tais kom tsim nyog, raws li kev ntsuas yav dhau los ntawm kev hloov pauv sib sib zog nqus siv cov poov xab-pom pom RBD, ntau qhov kev hloov pauv muaj tsawg lossis tsis cuam tshuam rau cov khoom siv no (7 ) (Daim duab 1, A thiab B sawv cev rau qhov poob ntawm ACE2 affinity, thaum daim duab S2 sawv cev rau qhov txo qis hauv RBD qhia.
(A) Mapping the antibody in REGN-COV2.Cov kab kos nyob rau sab laug qhia txog kev khiav tawm ntawm txhua qhov chaw hauv RBD (cov lej ntawm txhua qhov kev hloov pauv ntawm txhua qhov chaw).Daim duab logo ntawm sab xis qhia tau hais tias qhov chaw khiav tawm muaj zog (liab kab hauv qab).Qhov siab ntawm txhua tsab ntawv yog sib npaug rau lub zog ntawm kev khiav tawm los ntawm kev hloov pauv ntawm cov amino acid, thiab qhov "kev khiav tawm qhab nia" ntawm 1 rau txhua qhov kev hloov pauv sib raug rau kev khiav tawm tag.Qhov ntsuas y-axis txawv rau txhua kab, yog li, piv txwv li, E406W khiav tawm tag nrho REGN cov tshuaj tiv thaiv, tab sis nws yog qhov pom tseeb tshaj plaws rau cocktails vim tias nws dhau los ntawm lwm qhov chaw khiav tawm ntawm cov tshuaj tiv thaiv tus kheej.Rau qhov scalable version, S2, A thiab B, yog siv los xim daim ntawv qhia los ntawm kev hloov pauv cuam tshuam li cas rau kev qhia ntawm folded RBD.S2, C thiab D yog siv los faib cov kev cuam tshuam ntawm ACE2 affinity thiab RBD qhia ntawm txhua qhov kev hloov pauv tau pom nyob rau hauv cov kab mob sib kis.(B) Raws li qhia hauv (A), kos LY-CoV016.(C) Siv spike-pseudotyped lentiviral particles los xyuas cov kev hloov pauv tseem ceeb hauv qhov kev ntsuam xyuas nruab nrab.Peb tau xaiv los txheeb xyuas qhov kev hloov pauv uas tau kwv yees tias yuav muaj kev cuam tshuam ntau dua lossis muaj nyob ntawm qhov muaj zaus hauv SARS-CoV-2 cais tawm (xws li N439K) hauv kev ncig.Txhua lub ntsiab lus sawv cev rau qhov nce ntxiv ntawm qhov nruab nrab inhibitory concentration (IC50) ntawm kev hloov pauv txheeb ze rau lub ncov ntawm cov tsiaj qus uas tsis muaj kev hloov pauv (WT) uas muaj D614G.Cov kab xiav dashed 1 sawv cev rau cov txiaj ntsig nruab nrab zoo ib yam li WT, thiab tus nqi> 1 sawv cev rau kev ua kom tsis muaj zog ntxiv.Cov xim ntawm cov dot qhia seb koj puas xav khiav tawm ntawm daim ntawv qhia.Cov dots qhia tau hais tias txij li thaum IC50 nyob sab nraum lub dilution series siv, ntau qhov kev hloov pauv raug kuaj xyuas (saum toj lossis qis dua).Feem ntau cov mutants raug sim nyob rau hauv duplicate, yog li muaj ob lub ntsiab lus.Qhov ua tiav qhov nkhaus neutralization yog qhia hauv daim duab 2. S3.Ib tsab ntawv luv luv ntawm cov amino acid residues yog raws li nram no: A, Ala;C, cysteine;D, Asp;E, Glu;F, Peb;G, Gly;H, nws;Ib, Ile;K, lisine;L, Liu;Metropolis N, Assen;P, Pro;Q, Gln;R, Arg;S, Ser;T, Thr;V, Val;W, tryptophan;thiab Y, Tyr.
Txhawm rau txheeb xyuas cov txiaj ntsig antigenic ntawm cov kev hloov pauv tseem ceeb, peb tau ua qhov kev ntsuam xyuas nruab nrab siv panicle pseudotyped lentiviral particles, thiab pom tias muaj qhov sib xws ntawm cov tshuaj tiv thaiv kab mob binding khiav tawm daim ntawv qhia thiab qhov kev ntsuam xyuas nruab nrab (Daim duab 1C thiab daim duab S3).Raws li xav tau los ntawm daim ntawv qhia REGN-COV2 antibody, qhov kev hloov ntawm txoj hauj lwm 486 tsuas yog neutralized los ntawm REGN10933, thaum kev hloov ntawm txoj hauj lwm 439 thiab 444 tsuas yog neutralized los ntawm REGN10987, yog li cov kev hloov no tsis tuaj yeem khiav tawm.Tab sis E406W tau dim ntawm ob lub REGN-COV2 cov tshuaj tiv thaiv, yog li nws kuj tau dim ntawm qhov sib xyaw ua ke.Los ntawm kev txheeb xyuas cov qauv thiab kev xaiv tus kab mob khiav tawm, Regeneron ntseeg tias tsis muaj ib qho kev hloov pauv ntawm cov amino acid tuaj yeem khiav tawm ntawm ob cov tshuaj tiv thaiv kab mob hauv cov dej cawv (11, 12), tab sis peb daim ntawv qhia tiav qhia E406W raws li kev hloov pauv ntawm cocktail.E406W cuam tshuam rau REGN-COV2 cov tshuaj tiv thaiv kab mob hauv ib txoj kev tshwj xeeb, thiab tsis cuam tshuam nrog kev ua haujlwm ntawm RBD, vim tias nws tsuas yog txo qis cov nyhuv neutralization ntawm LY-CoV016 (Daim duab 1C) thiab titer ntawm spiked pseudotyped lentiviral hais (Daim duab S3F).
Txhawm rau tshawb xyuas seb peb daim ntawv qhia kev khiav tawm puas zoo ib yam nrog kev hloov pauv ntawm cov kab mob nyob rau hauv kev xaiv tshuaj tiv thaiv kab mob, peb thawj zaug tshawb xyuas cov ntaub ntawv ntawm Regeneron tus kab mob khiav dim kev sim, uas cov lus qhia tau loj hlob hauv kab lis kev cai ntawm tes nyob rau hauv muaj ib qho REGN10933 Lub vesicular. stomatitis virus (VSV), REGN10987 or REGN-COV2 cocktail (12).Txoj haujlwm no tau txheeb xyuas tsib qhov kev hloov pauv ntawm REGN10933, ob txoj kev khiav tawm ntawm REGN10987, thiab tsis muaj kev hloov pauv ntawm cocktail (Daim duab 2A).Cov kev hloov pauv uas tau xaiv los ntawm tag nrho xya kab lis kev cai ntawm tes yog qhov tseem ceeb hauv peb daim ntawv qhia kev khiav tawm, thiab kev hloov pauv ib leeg-nucleotide ntawm cov tsiaj qus-hom codon nyob rau hauv Wuhan-Hu-1 RBD ib ntus kuj siv tau (Daim duab 2B), qhia qhov txawv ntawm kev khiav tawm Concordance daim duab thiab tus kab mob evolution nyob rau hauv antibody siab nyob rau hauv cell kab lis kev cai.Nws yog ib qho tsim nyog sau cia tias E406W tsis tuaj yeem nkag mus tau los ntawm ib qho kev hloov pauv nucleotide, uas tuaj yeem piav qhia vim li cas Regeneron cocktail xaiv tsis tuaj yeem txheeb xyuas nws txawm tias qhov ua tau zoo ntawm RBD folding thiab ACE2 affinity.
(A) Nyob rau hauv lub xub ntiag ntawm cov tshuaj tiv thaiv, Regeneron siv panicle pseudotype VSV los xaiv tus kab mob khiav tawm ntawm cov kab lis kev cai ntawm tes (12).(B) Daim duab qhia kev khiav tawm, raws li pom hauv daim duab 1A, tab sis tsuas yog qhia cov kev hloov pauv nkag tau los ntawm ib qho kev hloov pauv nucleotide hauv Wuhan-Hu-1 ib ntus.Tsis-grey qhia txog kev hloov pauv hauv cov kab lis kev cai ntawm tes (liab), thiab cov neeg mob kis (xiav) ), lossis ob qho tib si (liab).Daim duab S5 qhia cov duab no, uas yog xim los ntawm qhov kev hloov pauv cuam tshuam li cas rau ACE2 affinity lossis RBD qhia.(C) Kinetics ntawm RBD mutation nyob rau hauv cov neeg mob kho nrog REGN-COV2 nyob rau 145th hnub ntawm tus kab mob (dub dotted ntsug kab).Qhov zaus ntawm kev sib txuas ntawm E484A thiab F486I tau nce, tab sis txij li E484A tsis yog kev hloov pauv hauv peb daim duab, nws tsis pom hauv lwm cov vaj huam sib luag.Saib daim duab.S4.(D) Kev khiav tawm ntawm kev hloov pauv uas tshwm sim hauv kab lis kev cai ntawm tes thiab cov neeg mob kis tau los ntawm ib qho nucleotide, thiab kev sib khi ntawm cov tshuaj tiv thaiv kev khiav tawm tsis ua rau muaj nqi loj rau ACE2 affinity [raws li ntsuas los ntawm cov poov xab zaub (7)].Txhua lub ntsiab lus yog kev hloov pauv, thiab nws cov duab thiab xim qhia seb nws puas tuaj yeem nkag mus thiab xaiv thaum tus kab mob loj hlob.Cov ntsiab lus ntawm sab xis ntau dua ntawm x-axis qhia tias muaj zog tiv thaiv kev sib khi khiav tawm;cov ntsiab lus siab dua ntawm y-axis qhia siab dua ACE2 affinity.
Txhawm rau txiav txim siab seb Escape Atlas tuaj yeem txheeb xyuas qhov kev hloov pauv ntawm cov kab mob kis rau tib neeg, peb tau tshuaj xyuas cov ntaub ntawv sib sib zog nqus los ntawm cov neeg mob uas muaj kab mob tiv thaiv kab mob tsis tu ncua uas tau txais REGN-COV2 rau hnub 145 tom qab kuaj pom ntawm COVID-19 Kev Kho Mob (16).Kev kho mob lig tso cai rau tus neeg mob cov kab mob kis mus rau ntau haiv neeg, qee qhov yuav raug tsav los ntawm lub cev tsis muaj zog, vim tias tus neeg mob muaj qhov tsis muaj zog autoneutralizing antibody teb ua ntej kev kho mob (16).Tom qab kev tswj hwm ntawm REGN-COV2, qhov zaus ntawm tsib amino acid hloov pauv hauv RBD hloov pauv sai (Daim duab 2C thiab daim duab S4).Peb daim ntawv qhia kev khiav tawm tau pom tias peb qhov kev hloov pauv no tau khiav tawm REGN10933 thiab ib tus dim REGN10987 (Daim duab 2B).Nws yog tsim nyog sau cia tias tom qab kho cov tshuaj tiv thaiv kab mob, tsis yog txhua qhov kev hloov pauv tau hloov mus rau qhov chaw ruaj khov.Ntawm qhov tsis sib xws, muaj qhov nce thiab poob ntawm kev sib tw (Daim duab 2C).Cov qauv no tau pom nyob rau hauv cov kev hloov pauv sab hauv ntawm kev hloov pauv ntawm lwm cov kab mob (17, 18), tej zaum yog vim muaj kev sib tw ntawm cov caj ces tsis muaj caij tsheb thiab kab mob kis.Ob lub zog no zoo li ua lub luag haujlwm rau cov neeg mob uas muaj kab mob tsis tu ncua (Daim duab 2C thiab daim duab S4C): E484A (tsis yog kev hloov pauv hauv peb daim duab) thiab F486I (kev khiav tawm REGN10933) kev caij tsheb dawb tom qab kev kho mob, thiab kab mob kab mob nqa N440D Thiab Q493K (kev khiav tawm REGN10987 thiab REGN10933, feem) thawj zaug sib tw nrog REGN10933 khiav tawm mutant Y489H, thiab tom qab ntawd tau sib tw nrog cov caj ces nqa E484A thiab F486I thiab Q493K.
Peb ntawm plaub qhov kev hloov pauv hloov pauv hauv cov neeg mob tau kho nrog REGN-COV2 tsis tau txheeb xyuas hauv Regeneron tus kab mob ntawm tes kab lis kev cai xaiv (Daim duab 2B), uas qhia txog qhov zoo ntawm daim ntawv qhia tiav.Kev xaiv tus kab mob tsis tiav vim lawv tsuas tuaj yeem txheeb xyuas cov kev hloov pauv uas tau xaiv hauv qhov kev sim kab lis kev cai ntawm tes.Ntawm qhov tsis sib xws, daim ntawv qhia ua tiav piav qhia txog txhua qhov kev hloov pauv, uas yuav suav nrog kev hloov pauv los ntawm cov laj thawj tsis cuam tshuam nrog kev kho mob, tab sis cuam tshuam rau cov tshuaj tiv thaiv kab mob.
Tau kawg, kev hloov pauv ntawm cov kab mob cuam tshuam los ntawm kev txwv kev ua haujlwm thiab lub siab kom tsis txhob muaj cov tshuaj tiv thaiv kab mob.Cov kev hloov pauv thiab cov neeg mob xaiv hauv kab lis kev cai ntawm tes ib txwm ua tau raws li cov hauv qab no: lawv khiav tawm cov tshuaj tiv thaiv kab mob, tuaj yeem nkag los ntawm ib qho kev hloov pauv nucleotide, thiab tsis muaj nqi tsawg lossis tsis muaj nqi rau ACE2 affinity [los ntawm kev sib sib zog nqus yav dhau los pom siv cov poov xab Scanning ntsuas RBD (7 )] (Daim duab 2D thiab daim duab S5).Yog li, daim ntawv qhia ua tiav ntawm qhov kev hloov pauv cuam tshuam li cas rau cov biochemical phenotypes tseem ceeb ntawm RBD (xws li ACE thiab antibody binding) tuaj yeem siv los ntsuas txoj hauv kev rau tus kab mob evolution.Ib qho kev ceeb toom yog tias nyob rau hauv lub sij hawm evolutionary ntev, raws li tau pom nyob rau hauv kev tiv thaiv kab mob thiab kev khiav tawm ntawm cov tshuaj, vim muaj kev cuam tshuam ntawm epistatic, qhov chaw kam rau kev hloov pauv yuav hloov (19-21).
Daim ntawv qhia ua tiav tso cai rau peb los soj ntsuam cov kev hloov pauv uas twb muaj lawm hauv SARS-CoV-2 circulating.Peb tau tshuaj xyuas tag nrho cov tib neeg uas tau txais los ntawm SARS-CoV-2 ib ntus txij li Lub Ib Hlis 11, 2021 thiab pom tias coob tus ntawm RBD hloov pauv tau dim ib lossis ntau cov tshuaj tiv thaiv (Daim duab 3).Txawm li cas los xij, qhov kev hloov pauv nkaus xwb tam sim no hauv> 0.1% ntawm qhov sib lawv liag yog REGN10933 dim mutant Y453F [0.3% ntawm qhov sib lawv liag;saib (12)], REGN10987 khiav tawm mutant N439K [1.7% ntawm qhov sib lawv liag;saib Figure 1C and (22)], And LY-CoV016 escape mutation K417N (0.1% sequence; see also Figure 1C).Y453F muaj feem cuam tshuam nrog kev tawm tsam ywj pheej ntsig txog mink ua liaj ua teb hauv Netherlands thiab Denmark (23, 24);Nws yog ib qho tsim nyog sau cia tias mink ntu nws tus kheej qee zaum muaj lwm yam kev hloov pauv, xws li F486L (24).N439K yog nrov heev nyob rau hauv cov teb chaws Europe, thiab ua ib tug loj ib feem ntawm qhov sib lawv liag ntawm Scotland thiab Ireland nyob rau hauv cov teb chaws Europe (22, 25).K417N muaj nyob rau hauv kab B.1.351 thawj zaug pom hauv South Africa (10).Lwm qhov kev hloov pauv ntawm kev txhawj xeeb tam sim no yog N501Y, uas tam sim no nyob rau hauv B.1.351 thiab tseem nyob hauv B.1.1.7 kab keeb thawj zaug tau txheeb xyuas hauv UK (9).Peb daim ntawv qhia qhia tau hais tias N501Y tsis muaj kev cuam tshuam rau REGN-COV2 antibody, tab sis tsuas yog muaj feem cuam tshuam rau LY-CoV016 (Figure 3).
Rau txhua cov tshuaj tiv thaiv kab mob lossis tshuaj tiv thaiv kab mob sib xyaw ua ke, txij li Lub Ib Hlis 11, 2021, ntawm 317,866 tus neeg muaj txiaj ntsig zoo los ntawm SARS-CoV-2 sequences ntawm GISAID (26), kev sib raug zoo ntawm kev khiav tawm ntawm txhua qhov kev hloov pauv thiab nws qhov zaus.Nws yog cim.REGN-COV2 cocktail dim kev hloov pauv E406W yuav tsum muaj ntau yam kev hloov pauv nucleotide hauv Wuhan-Hu-1 RBD ib ntus, thiab tsis tau pom nyob rau hauv GISAID ib ntus.Lwm qhov kev hloov pauv ntawm qhov seem E406 (E406Q thiab E406D) tau pom nrog suav nrog tsawg zaus, tab sis cov amino acids mutant no tsis yog ib qho kev hloov pauv nucleotide nyob deb ntawm W.
Raws li xav tau, kev khiav tawm kev hloov pauv feem ntau tshwm sim hauv cov tshuaj tiv thaiv-RBD interface.Txawm li cas los xij, tus qauv ib leeg tsis txaus los twv seb qhov kev hloov pauv twg los daws qhov kev khiav tawm.Piv txwv li, LY-CoV016 siv nws txoj hlua hnyav thiab lub teeb los khi rau qhov dav dav uas sib tshooj ntawm ACE2 khi nto, tab sis txoj kev khiav tawm cuam tshuam nrog kev hloov pauv hauv RBD residues nyob rau hauv qhov hnyav chain complementarity txiav txim siab cheeb tsam (Daim duab 4A thiab daim duab S6, E rau G).Hauv qhov sib piv, kev khiav tawm ntawm REGN10933 thiab REGN10987 feem ntau tshwm sim ntawm RBD residues stacked ntawm lub interface ntawm cov tshuaj tiv thaiv hnyav thiab lub teeb chains (Daim duab 4A thiab daim duab S6, A txog D).Qhov kev hloov pauv E406W uas tau khiav tawm ntawm REGN-COV2 sib tov tshwm sim ntawm cov khoom seem uas tsis sib cuag nrog cov tshuaj tiv thaiv kab mob (Daim duab 4, A thiab B).Txawm hais tias E406 yog tus qauv ze dua rau LY-CoV016 (Figure 4B thiab Figure S6H), E406W kev hloov pauv muaj qhov cuam tshuam me dua ntawm cov tshuaj tiv thaiv (Daim duab 1, B thiab C), qhia tias qhov tshwj xeeb ntev-ntau cov qauv txheej txheem yog los tiv thaiv REGN. -Cov 2 antibody (Fig S6I).Hauv cov ntsiab lus, kev hloov pauv ntawm RBD residues nyob rau hauv kev sib cuag nrog cov tshuaj tiv thaiv tsis tas yuav kho kom haum rau kev khiav tawm, thiab qee qhov kev hloov pauv tseem ceeb tshwm sim ntawm cov khoom seem uas tsis sib cuag nrog cov tshuaj tiv thaiv (Daim duab 4B thiab daim duab S6, D thiab G).
(A) Daim duab khiav tawm tau npaj rau ntawm RBD qauv khi los ntawm cov tshuaj tiv thaiv.[REGN10933 thiab REGN10987: Protein Database (PDB) ID 6XDG (11);LY-CoV016: PDB ID 7C01 (13)].Qhov sib txawv ntawm qhov hnyav thiab lub teeb chains ntawm cov tshuaj tiv thaiv yog pom raws li cov duab kos duab xiav, thiab cov xim ntawm qhov chaw ntawm RBD qhia lub zog ntawm kev hloov pauv-kho tawm ntawm qhov chaw no (dawb qhia tias tsis muaj kev khiav tawm, thiab liab qhia tias muaj zog tshaj. khiav qhov chaw ntawm cov tshuaj tiv thaiv los yog sib tov).Cov chaw uas tsis ua haujlwm hloov pauv tau greyed tawm.(B) Rau txhua qhov tshuaj tiv thaiv, faib qhov chaw raws li cov tshuaj tiv thaiv kab mob ncaj qha (tsis yog hydrogen atoms hauv 4Å ntawm cov tshuaj tiv thaiv), cov tshuaj tiv thaiv kab mob sib kis (4 txog 8Å) lossis cov tshuaj tiv thaiv kab mob distal (> 8Å).Txhua lub ntsiab lus sawv cev rau ib qhov chaw, muab faib ua kev khiav tawm (liab) lossis tsis khiav (dub).Cov kab grey dashed sawv cev rau tus nqi tseem ceeb uas siv los faib lub xaib raws li kev khiav tawm lossis tsis yog kev khiav tawm (kom paub meej, saib Cov Khoom Siv thiab Cov Txheej Txheem).Cov lej liab thiab dub qhia tias muaj pes tsawg qhov chaw hauv txhua pawg tau khiav tawm lossis khiav tawm.
Nyob rau hauv txoj kev tshawb no, peb tau ua tiav daim ntawv qhia txog kev hloov pauv uas khiav tawm peb qhov loj los tiv thaiv SARS-CoV-2 antibodies.Cov duab qhia chaw no qhia tau hais tias yav dhau los tus yam ntxwv ntawm kev khiav tawm kev hloov pauv tsis tiav.Tsis muaj ib qho kev hloov pauv ntawm cov amino acid uas tuaj yeem khiav tawm ntawm ob lub tshuaj tiv thaiv kab mob hauv REGN-COV2 cocktail tau raug txheeb xyuas, thiab lawv tsis tau txheeb xyuas feem ntau ntawm cov neeg mob tsis tu ncua kho nrog cov dej cawv.kev hloov pauv.Tau kawg, peb daim ntawv qhia tseem tsis tau teb cov lus nug tseem ceeb tshaj plaws: Puas yog SARS-CoV-2 tsim kev tiv thaiv ntau rau cov tshuaj tiv thaiv no?Tab sis dab tsi yog qhov tseeb yog tias nws txhawj xeeb tias ntau qhov kev hloov pauv hloov pauv tau cuam tshuam me ntsis ntawm RBD folding lossis receptor affinity, thiab twb muaj qee qhov kev hloov pauv qis hauv cov kab mob kis.Thaum kawg, nws yuav tsum tau tos thiab saib seb qhov kev hloov pauv ntawm SARS-CoV-2 yuav kis tau li cas thaum nws kis mus rau cov pejxeem.Peb txoj haujlwm yuav pab "kev soj ntsuam" los ntawm kev piav qhia tam sim ntawm qhov cuam tshuam ntawm kev hloov pauv tau cais los ntawm kev soj ntsuam kab mob genome.
Nov yog ib tsab xov xwm qhib nkag tau muab faib raws li cov ntsiab lus ntawm Creative Commons Attribution License.Tsab ntawv tso cai txwv tsis pub siv, kev faib tawm, thiab luam tawm hauv ib qho nruab nrab raws li qhov xwm txheej uas cov haujlwm qub raug suav hais tias yog.
Nco tseg: Peb tsuas yog hais kom koj muab koj tus email chaw nyob kom tus neeg koj pom zoo rau nplooj ntawv paub tias koj xav kom lawv pom email thiab nws tsis yog spam.Peb yuav tsis ntes tej email chaw nyob.
Lo lus nug no yog siv los ntsuas seb koj puas yog tus qhua thiab tiv thaiv tsis siv neeg xa spam.
Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
Daim ntawv qhia ua tiav ntawm SARS-CoV-2 kev hloov pauv uas khiav tawm ntawm Regeneron monoclonal antibody sib xyaw pab piav qhia txog kev hloov pauv ntawm tus kab mob hauv kev kho cov neeg mob.
Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
Daim ntawv qhia ua tiav ntawm SARS-CoV-2 kev hloov pauv uas khiav tawm ntawm Regeneron monoclonal antibody sib xyaw pab piav qhia txog kev hloov pauv ntawm tus kab mob hauv kev kho cov neeg mob.
© 2021 American Association rau Advancement of Science.tag nrho cov cai.AAAS yog ib tug khub ntawm HINARI, AGORA, OARE, CHORUS, CLOCKSS, CrossRef thiab COUNTER.Science ISSN 1095-9203.
Post lub sij hawm: Feb-24-2021