Amasosha omzimba amaningana asevele esetshenziswa noma asathuthukiswa njengezindlela zokwelapha i-COVID-19.Ngokuvela kwezinhlobonhlobo ezintsha ze-acute acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), kubalulekile ukubikezela ukuthi zisazoba lula yini ekwelashweni kwamasosha omzimba.Inkanyezi et al.Kusetshenziswe umtapo wolwazi weyeast, ohlanganisa zonke izinguquko esizindeni esibophezelayo sesamukeli sakwa-SARS-CoV-2 esingeke siphazamise kakhulu ukubophezela kwesamukeli somsingathi (ACE2), kanye nemephu ukuthi lezi zinguquko zibathinta kanjani abathathu I-anti-SARS-CoV eyinhloko. -2 ukubopha ama-antibody.Lezi zibalo zikhomba ukuguquka kwesimo esibalekela ukubopha amasosha omzimba, okuhlanganisa ukuguqulwa okukodwa okuphunyuka kumasosha omzimba amabili kungxube ye-Regeneron antibody.Izinguquko eziningi ezibalekela i-antibody eyodwa ziyasabalala kubantu.
Ama-antibodies awukwelapha okungaba khona ekwelapheni i-acute acute respiratory syndrome 2 (SARS-CoV-2), kodwa akucaci ukuthi leli gciwane liyakhula ukuze libaleke engozini yalo.Lapha, senza imephu ukuthi zonke izinguquko eziku-SARS-CoV-2 receptor binding domain (RBD) zikuthinta kanjani ukubopheka kwe-REGN-COV2 cocktail ku-antibody LY-CoV016.Lawa mamephu aphelele aveze ukuguqulwa kwe-amino acid okugweme ngokuphelele ingxube ye-REGN-COV2, eyakhiwe ngamasosha omzimba amabili i-REGN10933 kanye ne-REGN10987 aqondise ama-epitopes esakhiwo ahlukene.Lezi zibalo ziphinde zihlonze ukuguqulwa kwegciwane ezigulini ezinegciwane eziphikelelayo ezilashwa nge-REGN-COV2 nangesikhathi sokukhetha ukuphunyuka kwegciwane le-in vitro.Ekugcineni, lezi zibalo ziveza ukuthi ukuguqulwa okuphunyuka ku-antibody eyodwa sekuvele kukhona ekujikelezeni kwezinhlobo ze-SARS-CoV-2.Lawa mamephu wokuphunyuka aphelele angachaza imiphumela yoguquko olubonwa ngesikhathi sokubhekwa kwegciwane.
Ama-antibodies athuthukiswa ukwelapha i-acute acute respiratory syndrome i-coronavirus 2 (SARS-CoV-2) (1).Ama-antibodies ngokumelene namanye amagciwane angenziwa angasebenzi ngokuguqulwa kwegciwane okukhethwe ngesikhathi sokwelashwa kweziguli ezithelelekile (2, 3) noma ukuguqulwa kwegciwane okusabalele emhlabeni wonke ukunikeza ukumelana nalo lonke igciwane.Ngakho-ke, ukunquma ukuthi yikuphi ukuguqulwa kwe-SARS-CoV-2 okungabalekela amasosha omzimba abalulekile kubalulekile ukuze kuhlolwe ukuthi ukuguqulwa kwezakhi zofuzo okubonwa ngesikhathi sokubhekwa kwegciwane kukuthinta kanjani ukusebenza kahle kokwelashwa kwamasosha omzimba.
Amasosha omzimba ahola kakhulu e-anti-SARS-CoV-2 aqondise kusizinda sokubopha i-viral receptor (RBD), esixhumanisa ukubopha i-angiotensin eguqula i-enzyme 2 (ACE2) receptor (5, 6).Muva nje, sithuthukise indlela ejulile yokuskena yokuguqula ukuze senze imephu ukuthi zonke izinguquko ze-RBD ziwuthinta kanjani umsebenzi wayo nokuqashelwa ngamasosha omzimba alwa namagciwane (7, 8).Le ndlela ihlanganisa ukudala umtapo wezincwadi eziguquguqukayo ze-RBD, ukuziveza ebusweni bemvubelo, nokusebenzisa ukuhlunga kwamaseli acushwe yi-fluorescence kanye nokulandelanisa okujulile ukuze kutholakale ukuthi ukuguqulwa ngakunye kukuthinta kanjani ukugoqa kwe-RBD, ukuhambisana kwe-ACE2 (kukalwa ochungechungeni lwe-titration), kanye nokubopha amasosha omzimba. (Umfanekiso S1A).Kulolu cwaningo, sisebenzise umtapo wezincwadi oguqukayo ophindaphindwayo ochazwe ku-(7), owakhiwa okuhlukile okunebhakhodi ye-RBD, ehlanganisa okungu-3804 kokungu-3819 okungenzeka kube nokuguqulwa kwe-amino acid.Umtapo wethu wezincwadi walungiswa kusukela kusizinda sofuzo se-RBD ye-Wuhan-Hu-1 yasekuqaleni eyedwa.Yize imvamisa yama-mutant ambalwa anda, zisamele ukulandelana okujwayelekile kwe-RBD (9, 10).Sidwebe okubili koguquko lwango-2034 olungaphazamisi kakhulu ukugoqa kwe-RBD kanye nokubophezela kwe-ACE (7) ukuthi ungayidlulisa kanjani i-REGN-COV2 cocktail (REGN10933 kanye ne-REGN10987) (11, 12) kanye ne-Eli Lilly's LY-CoV016 Ifomu lokuhlanganisa kabusha I-antibody ithinta indlela yokubopha amasosha omzimba (ebizwa nangokuthi i-CB6 noma i-JS016) (13) (Umfanekiso S1B).I-REGN-COV2 isanda kugunyazwa ukusetshenziswa okuphuthumayo kwe-COVID-19 (14), kuyilapho i-LY-CoV016 njengamanje ihlolwa isigaba sesi-3 somtholampilo (15).
[Glu406→Trp(E406W)] iphunyuke kakhulu engxubeni yamasosha omzimba amabili (Umfanekiso 1A).Imephu yokuphunyuka ye-LY-CoV016 iphinde yembula izinguquko eziningi zokuphunyuka kumasayithi ahlukene e-RBD (Umfanekiso 1B).Yize ezinye izinguquko zokubalekela zingakhinyabeza ikhono le-RBD lokubophezela ku-ACE2 noma liveze ngendlela egoqwe ngokufanelekile, ngokuya ngezilinganiso zangaphambilini zokuskena ukuguqulwa okujulile kusetshenziswa i-RBD eboniswa imvubelo, ukuguqulwa okuningi kokusebenza kunomthelela omncane noma akukho nhlobo kulezi zici ezisebenzayo (7 ) (Umfanekiso 1, A no-B umele ukulahlekelwa ukuhambisana kwe-ACE2, kuyilapho uMfanekiso S2 umele ukwehla kwesisho se-RBD.
(A) Ukwenza imephu ye-antibody ku-REGN-COV2.Igrafu yomugqa kwesokunxele ibonisa ukubaleka kusayithi ngalinye ku-RBD (inani lakho konke ukuguqulwa kusayithi ngalinye).Isithombe selogo kwesokudla sibonisa indawo yokubalekela eqinile (dwebela onsomi).Ubude bohlamvu ngalunye bulingana namandla okuphunyuka okulamula ukuguqulwa kwe-amino acid, futhi "isikolo sokuphunyuka" esingu-1 sokuguqulwa ngakunye sihambisana nokubaleka okuphelele.Isikali sika-y-axis sihlukile kumugqa ngamunye, ngakho-ke, isibonelo, i-E406W ibalekela wonke amasosha omzimba e-REGN, kodwa kusobala kakhulu kuma-cocktails ngoba ikhungethwe amanye amasayithi okuphunyuka amasosha omzimba ngamanye.Okwenguqulo engakala, i-S2, A no-B, isetshenziselwa ukufaka umbala kumephu ngokuthi ukuguqulwa kwezakhi zofuzo kuyithinta kanjani inkulumo ye-RBD egoqiwe.I-S2, C no-D isetshenziselwa ukusabalalisa umthelela ku-ACE2 affinity kanye nenkulumo ye-RBD phakathi kwakho konke ukuguqulwa okubonwa ekuhlukaniseni amagciwane ajikelezayo.(B) Njengoba kukhonjisiwe ku-(A), dweba i-LY-CoV016.(C) Sebenzisa izinhlayiya ze-spike-pseudotyped lentiviral ukuze uqinisekise ukuguqulwa kokhiye ekuhlolweni kokungathathi hlangothi.Sikhethe ukuqinisekisa ukuguqulwa kwezakhi zofuzo okubikezelwa ukuthi kunomthelela omkhulu noma okukhona ngemvamisa ephezulu kuma-SARS-CoV-2 isolate (njenge-N439K) ekuhambeni.Iphuzu ngalinye limelela ukwanda okugoqekayo kwe-median inhibitory concentration (IC50) yokuguqulwa okuhlobene nokuphakama kohlobo lwasendle olungashintshiwe (WT) oluqukethe i-D614G.Umugqa woku-1 onedeshi eluhlaza okwesibhakabhaka umele umthelela wokungathathi hlangothi ofana ne-WT, futhi inani> 1 limelela ukumelana nokwenyuka kokungathathi hlangothi.Umbala wechashazi ubonisa ukuthi uyafuna yini ukuphunyuka kumephu.Amachashazi abonisa ukuthi njengoba i-IC50 ingaphandle kochungechunge lwe-dilution olusetshenzisiwe, ushintsho oluningi luyahlolwa (umkhawulo ophezulu noma ophansi).Iningi lezinguquko lihlolwa ngokuphindwe kabili, ngakho-ke kukhona amaphuzu amabili.Ijika eliphelele le-neutralization liboniswa kuMfanekiso 2. S3.Izifinyezo ezinohlamvu olulodwa lwezinsalela ze-amino acid zimi kanje: A, Ala;C, Cysteine;D, Asp;E, Glu;F, Phe;G, Gly;H, eyakhe;Mina, Ile;K, i-lysine;L, Liu;Metropolis N, Assen;P, Pro;Q, Gln;R, Arg;S, Ser;T, Thr;V, Val;W, tryptophan;kanye no-Y, Tyr.
Ukuze kuqinisekiswe umthelela we-antigenic wokuguqulwa kokhiye, senze i-neutralization assay sisebenzisa izinhlayiya ze-panicle pseudotyped lentiviral, futhi sathola ukuthi kukhona ukuvumelana phakathi kwemephu yokuphunyuka ebopha ama-antibody kanye ne-neutralization assay (Umfanekiso 1C noFigure S3).Njengoba kulindelekile kumephu ye-antibody ye-REGN-COV2, ukuguqulwa endaweni engu-486 kwenziwa kuphela i-REGN10933, kuyilapho ukuguqulwa ezindaweni 439 kanye no-444 kwenziwa kuphela i-REGN10987, ngakho-ke lezi zinguquko azikwazi ukuphunyuka.Kodwa i-E406W yaphunyuka kumasosha omzimba amabili e-REGN-COV2, ngakho nayo yaphunyuka kakhulu engxubeni.Ngokuhlaziywa kwesakhiwo nokukhetha ukuphunyuka kwegciwane, u-Regeneron ukholelwa ukuthi akukho ukuguqulwa okukodwa kwe-amino acid okungabalekela amasosha omzimba amabili ku-cocktail (11, 12), kodwa imephu yethu ephelele ikhomba i-E406W njengokuguqulwa kokuphunyuka kwe-cocktail.I-E406W ithinta i-antibody ye-REGN-COV2 ngendlela eqondile, futhi ayiphazamisi kakhulu umsebenzi we-RBD, ngoba yehlisa kancane umphumela wokungathathi hlangothi we-LY-CoV016 (Umfanekiso 1C) kanye nesihloko sezinhlayiya ze-lentinoviral ezikhonjiwe ( Umfanekiso I-S3F).
Ukuze sihlole ukuthi ingabe imephu yethu yokuphunyuka iyahambisana yini nokuvela kwamagciwane ngaphansi kokukhethwa kwe-antibody, siqale sahlola idatha yokuhlolwa kokukhetha ukuphunyuka kwegciwane le-Regeneron, lapho inkulumo ethi spike yakhuliswa kusiko lamaseli phambi kwanoma iyiphi i-REGN10933 The vesicular. i-stomatitis virus (VSV), REGN10987 noma i-REGN-COV2 cocktail (12).Lo msebenzi uhlonze izinguquko zokuphunyuka ezinhlanu ezivela ku-REGN10933, ukuguqulwa okubili kokuphunyuka okuvela ku-REGN10987, futhi akukho zinguquko ezivela ku-cocktail (Umfanekiso 2A).Ukuguqulwa kwezakhi zofuzo ezikhethwe yiwo wonke amasiko amaseli ayisikhombisa kugqanyisiwe kumephu yethu yokuphunyuka, futhi ukuguqulwa kwe-nucleotide eyodwa ye-codon yohlobo lwasendle ngokulandelana kwe-Wuhan-Hu-1 RBD nakho kuyafinyeleleka (Umfanekiso 2B), okubonisa umehluko phakathi kokuphunyuka kwe-Concordance. igrafu kanye nokuvela kwegciwane ngaphansi kwengcindezi ye-antibody kusiko lamaseli.Kuyaqapheleka ukuthi i-E406W ayikwazi ukufinyelelwa ngezinguquko ze-nucleotide eyodwa, ezingase zichaze ukuthi kungani ukukhethwa kwe-cocktail ye-Regeneron kungakwazi ukuyikhomba naphezu kokubekezelela okuhle kokugoqa kwe-RBD kanye nokuhambisana kwe-ACE2.
(A) Lapho kukhona amasosha omzimba, i-Regeneron isebenzisa i-panicle pseudotype VSV ukukhetha ukuguqulwa kokuphunyuka kwegciwane kusiko lamaseli (12).(B) Umdwebo wokuphunyuka, njengoba kukhonjisiwe kuMfanekiso 1A, kodwa ubonisa kuphela izinguquko ezifinyeleleka ngoshintsho olulodwa lwe-nucleotide ngokulandelana kwe-Wuhan-Hu-1.Okungampunga kubonisa ukuguquka kwesiko lamaseli (obomvu), kanye neziguli ezinegciwane (okuluhlaza okwesibhakabhaka)), noma kokubili (okunsomi).Umfanekiso S5 ubonisa lawa magrafu, anemibala ngendlela ukuguqulwa kwezakhi zofuzo okuthinta ngayo ukuhambisana kwe-ACE2 noma isisho se-RBD.(C) I-Kinetics yokuguqulwa kwe-RBD ezigulini ezelashwa nge-REGN-COV2 ngosuku lwe-145 lokutheleleka (umugqa oqondile onamachashazi amnyama).Imvamisa yokuxhumanisa phakathi kwe-E484A ne-F486I inyukile, kodwa njengoba i-E484A ingelona ukuguqulwa kokuphunyuka kumfanekiso wethu, ayiboniswa kwamanye amaphaneli.Bheka futhi umfanekiso.S4.(D) Ukuguqulwa kokuphunyuka okwenzeka kusiko lwamaseli kanye neziguli ezithelelekile zifinyeleleka nge-nucleotide eyodwa, futhi ukuboshwa kwamasosha omzimba akubangeli noma yiziphi izindleko ezinkulu ku-ACE2 affinity [njengoba kulinganiswa ngendlela yokubonisa imvubelo (7)].Iphuzu ngalinye liwuguquko, futhi ukuma nombala walo kubonisa ukuthi lingafinyelelwa futhi likhethwe phakathi nokukhula kwegciwane.Amaphoyinti angakwesokunene engeziwe ku-x-eksisi akhombisa ukuphunyuka okubopha amasosha omzimba aqinile;amaphuzu aphezulu ku-y-eksisi abonisa ukuhambisana kwe-ACE2 okuphezulu.
Ukuze sinqume ukuthi i-Escape Atlas ingakwazi yini ukuhlaziya ukuvela kwamagciwane athelela abantu, sihlole idatha elandelanayo ejulile evela esigulini esinegciwane esiphikelelayo esine-immunocompromised esathola i-REGN-COV2 ngosuku lwe-145 ngemuva kokutholakala kwe-COVID-19 Treatment (16).Ukwelashwa kwakamuva kuvumela inani legciwane lesiguli ukuthi liqongelele ukuhlukahluka kofuzo, okunye okungaqhutshwa ukucindezelwa kwamasosha omzimba, ngoba isiguli sinokusabela okubuthakathaka kwe-autoneutralizing antibody ngaphambi kokwelashwa (16).Ngemuva kokuphathwa kwe-REGN-COV2, imvamisa yokuguqulwa kwama-amino acid amahlanu ku-RBD yashintsha ngokushesha (Umfanekiso 2C kanye noMfanekiso S4).Imephu yethu yokuphunyuka ibonise ukuthi ezintathu zalezi zinguquko ziphunyukile ku-REGN10933 futhi eyodwa yaphunyuka ku-REGN10987 (Umfanekiso 2B).Kuyaqapheleka ukuthi ngemuva kokwelashwa kwe-antibody, akuzona zonke izinguquko ezidluliselwe endaweni engaguquki.Ngokuphambene nalokho, kukhona ukukhuphuka nokuwa kokuncintisana (Umfanekiso 2C).Le phethini ibonwe ekuziphendukeleni kwemvelo kwangaphakathi kwezindimbane eziguquguqukayo zamanye amagciwane (17, 18), okungenzeka ngenxa yokuncintisana phakathi kwezakhi zofuzo ezihamba mahhala kanye nemigqa yegciwane.Womabili lawa mandla abonakala edlala indima ezigulini ezinokutheleleka okungapheli (Umfanekiso 2C kanye noMfanekiso S4C): E484A (hhayi ukuguqulwa kokuphunyuka kumdwebo wethu) kanye ne-F486I (ukubalekela i-REGN10933) ukuhamba mahhala ngemva kokwelashwa, kanye nemigqa yegciwane ephethe i-N440D Futhi I-Q493K (ebalekela i-REGN10987 kanye ne-REGN10933, ngokulandelanayo) yaqale yaqhudelana ne-REGN10933 yokubalekela i-mutant Y489H, yase iqhudelana nohlu oluphethe i-E484A ne-F486I ne-Q493K.
Izinguquko ezintathu kwezine zokubalekela ezigulini ezilashwa nge-REGN-COV2 azizange zihlonzwe ekukhethweni kwegciwane le-Regeneron cell culture (Umfanekiso 2B), okubonisa okuhle kwemephu ephelele.Ukukhethwa kwegciwane akuphelele ngoba angakwazi ukuhlonza kuphela noma yikuphi ukuguqulwa okukhethwe ngokungahleliwe kulokho kuhlolwa kwesiko leseli.Ngokuphambene, imephu ephelele ichaza konke ukuguqulwa kwezakhi zofuzo, okungase kuhlanganise ukuguqulwa okubangelwa izizathu ezingahlobene nokwelashwa, kodwa kuthinte ngephutha ukubopha amasosha omzimba.
Yiqiniso, ukuvela kwamagciwane kuthinteka ukulinganiselwa kokusebenza kanye nengcindezi yokugwema amasosha omzimba.Ukuguqulwa kwezakhi zofuzo kanye neziguli ezikhethwa kusiko lamaseli zihlala zihlangabezana nalezi zindlela ezilandelayo: zibalekela ukubopha amasosha omzimba, zingangena ngoshintsho olulodwa lwe-nucleotide, futhi zibe nezindleko ezincane noma zingabikho nhlobo ku-ACE2 affinity [ngokuguqulwa okujulile okudlule okuboniswe kusetshenziswa isikali seyeast Scanning RBD (7 )] (Figure 2D and Figure S5).Ngakho-ke, imephu ephelele yokuthi ukuguqulwa kwezakhi zofuzo kuwathinta kanjani ama-phenotypes we-biochemical we-RBD (okufana ne-ACE nokubopha amasosha omzimba) kungasetshenziswa ukuhlola izindlela ezingaba khona zokuvela kwegciwane.Enye i-caveat ukuthi esikhathini eside sokuziphendukela kwemvelo, njengoba kubonakala ekuvikelekeni kwegciwane kanye nokuphunyuka kwezidakamizwa, ngenxa yokusebenzisana kwe-epistatic, isikhala sokubekezelela ukuguqulwa kwezakhi zofuzo singashintsha (19-21).
Imephu ephelele isivumela ukuthi sihlole izinguquko zokuphunyuka ezikhona ku-SARS-CoV-2 ejikelezayo.Sihlole konke ukulandelana okutholakala komuntu kwe-SARS-CoV-2 kusukela ngomhlaka-11 Januwari 2021 futhi sathola ukuthi inani elikhulu lokuguqulwa kwe-RBD liphunyuke kumasosha omzimba oyedwa noma ngaphezulu (Umfanekiso 3).Nokho, ukuphela kokuguqulwa kokuphunyuka okukhona kokuthi >0.1% wokulandelana i-REGN10933 escape mutant Y453F [0.3% yokulandelana;bheka (12)], REGN10987 balekela i-mutant N439K [1.7% yokulandelana;bheka Umfanekiso 1C kanye (22)], Kanye ne-LY-CoV016 yokubalekela ukuguqulwa kwe-K417N (ukulandelana okungu-0.1%; bona futhi Umfanekiso 1C).I-Y453F ihlotshaniswa nokuqubuka okuzimele okuhlobene namapulazi e-mink eNetherlands naseDenmark (23, 24);kuyafaneleka ukuqaphela ukuthi ukulandelana kwe-mink ngokwayo ngezinye izikhathi kuqukethe ezinye izinguquko zokubalekela, njenge-F486L (24).I-N439K idume kakhulu eYurophu, futhi yenza ingxenye enkulu yokulandelana okuvela eScotland nase-Ireland eYurophu (22, 25).I-K417N ikhona ohlwini lozalo lwe-B.1.351 olwatholwa okokuqala eNingizimu Afrika (10).Okunye ukuguqulwa kokukhathazeka kwamanje yi-N501Y, ekhona ku-B.1.351 futhi futhi ohlwini lozalo lwe-B.1.1.7 oluhlonzwe ekuqaleni e-UK (9).Imephu yethu ibonisa ukuthi i-N501Y ayinawo umthelela kumasosha omzimba we-REGN-COV2, kodwa inomthelela omaphakathi kuphela ku-LY-CoV016 (Umfanekiso 3).
Ngenhlanganisela ngayinye ye-antibody noma i-antibody, kusukela ngoJanuwari 11, 2021, phakathi kokulandelana kwekhwalithi ephezulu kwe-SARS-CoV-2 okutholwe umuntu kwekhwalithi ephezulu okungu-317,866 ku-GISAID (26), ubudlelwano phakathi kwemiphumela yokuphunyuka kokuguqulwa ngakunye kanye nemvamisa yakhona .Imakiwe.I-REGN-COV2 cocktail yokuphunyuka kwe-E406W idinga izinguquko eziningi ze-nucleotide ngokulandelana kwe-Wuhan-Hu-1 RBD, futhi ayibonwa ngokulandelana kwe-GISAID.Okunye ukuguqulwa kwezinsalela ze-E406 (E406Q kanye ne-E406D) kwabonwa ngokubalwa kwefrikhwensi ephansi, kodwa lawa ma-amino acid aguqukayo awawona uguquko olulodwa lwe-nucleotide olukude ne-W.
Njengoba kulindelekile, ukuguqulwa kokuphunyuka kuvame ukuvela kusixhumi esibonakalayo se-antibody-RBD.Nokho, isakhiwo sisodwa akwanele ukubikezela ukuthi yiziphi izinguquko eziholela ekuphunyukeni.Isibonelo, i-LY-CoV016 isebenzisa amaketango ayo asindayo futhi alula ukuhlanganisa isiqephu esibanzi esidlula indawo ebophayo ye-ACE2, kodwa inqubo yokuphunyuka ihilela ukuguqulwa kwezinsalela ze-RBD endaweni enquma ukuhambisana kweketango elisindayo (Umfanekiso 4A kanye noMfanekiso S6, E kuya G).Ngokuphambene, ukuphunyuka ku-REGN10933 kanye ne-REGN10987 ikakhulukazi kwenzeke ezinsalela ze-RBD ezistakwe ekuxhumaneni kwe-antibody amaketango asindayo nalula (Umfanekiso 4A kanye noMfanekiso S6, A ukuya ku-D).Ukuguqulwa kwe-E406W okuphunyuke kungxube ye-REGN-COV2 kwenzeke ezinsalela ebezingathintani nanoma yiliphi i-antibody (Umfanekiso 4, A no-B).Yize i-E406 isondele ngokwesakhiwo ku-LY-CoV016 (Umfanekiso 4B kanye noMfanekiso S6H), ukuguqulwa kwe-E406W kunomphumela omncane kakhulu ku-antibody (Umfanekiso 1, B no-C), okubonisa ukuthi indlela ethile yesakhiwo sebanga elide iphikisana ne-REGN. - I-COV2 antibody (Figure S6I).Kafushane, ukuguqulwa kwezinsalela ze-RBD ezithinta amasosha omzimba akuhlali kulamula ukuphunyuka, futhi okunye ukuguqulwa okuphawulekayo kokuphunyuka kwenzeka ezinsalela ezingahlangene namasosha omzimba (Umfanekiso 4B kanye noMfanekiso S6, D no-G).
(A) Umdwebo wokuphunyuka ovezwa esakhiweni se-RBD esiboshwe yi-antibody.[REGN10933 kanye ne-REGN10987: Isizindalwazi Samaprotheni (PDB) ID 6XDG (11);I-LY-CoV016: I-PDB ID 7C01 (13)].Izizinda eziguquguqukayo zamaketango asindayo nalula e-antibody ziboniswa njengopopayi abaluhlaza okwesibhakabhaka, futhi umbala ongaphezulu kwe-RBD ubonisa amandla okubalekela okuqondiswa ukuguqulwa kule sayithi (okumhlophe kubonisa ukuthi akukho ukuphunyuka, futhi okubomvu kubonisa okuqine kakhulu. indawo yokubalekela i-antibody noma ingxube) .Amasayithi angashintshiwe ngokusebenza ampunga.(B) Ku-antibody ngayinye, hlukanisa isayithi njengokuthintana kwe-antibody okuqondile (ama-athomu angewona awe-hydrogen ngaphakathi kuka-4Å we-antibody), i-proximal antibody (4 kuya ku-8Å) noma i-distal antibody (> 8Å).Iphuzu ngalinye limelela isayithi, elihlukaniswe kwaba ukuphunyuka (okubomvu) noma okungaphunyuki (okumnyama).Umugqa wedeshi ompunga umele inani elibalulekile elisetshenziselwa ukuhlukanisa isayithi njengokubaleka noma ukungaphunyuki (ukuthola imininingwane, bheka Izinto Ezibalulekile kanye Nezindlela).Izinombolo ezibomvu nezimnyama zibonisa ukuthi mangaki amasayithi esigabeni ngasinye aphunyukile noma angaphunyuki.
Kulolu cwaningo, senze imephu ngokuphelele yokuguqulwa kwezakhi zofuzo ezigwema amasosha omzimba amathathu amakhulu e-anti-SARS-CoV-2.Lawa mamephu akhombisa ukuthi izici zangaphambilini zokuguqulwa kwe-escape aziphelele.Akukho ukuguqulwa okukodwa kwe-amino acid okungaphunyuka kumasosha omzimba amabili ku-cocktail ye-REGN-COV2 okuye kwahlonzwa, futhi akuzange kukhombe iningi leziguli ezithelelekayo ezilashwa nge-cocktail.ukuguquka kwezakhi zofuzo.Vele, imephu yethu ayikawuphenduli umbuzo ocindezela kakhulu: Ngabe i-SARS-CoV-2 izothuthukisa ukumelana nalawa ma-antibodies?Kodwa okuqinisekileyo ukuthi kuyakhathaza ukuthi izinguquko eziningi zokuphunyuka zinomthelela omncane ekugoqeni kwe-RBD noma ukusondelana kwesamukeli, futhi sekuvele kukhona ukuguqulwa kwezinga eliphansi kumagciwane ajikelezayo.Ekugcineni, kuyadingeka ukuthi ulinde futhi ubheke ukuthi yiziphi izinguquko ezizodluliselwa yi-SARS-CoV-2 lapho zisabalala phakathi kwabantu.Umsebenzi wethu uzosiza "ukubuka" ngokuchaza ngokushesha umthelela wokuguqulwa kwezakhi zofuzo ezihlukaniswa ukubhekwa kwe-viral genome.
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Qaphela: Sikucela kuphela ukuthi unikeze ikheli lakho le-imeyili ukuze umuntu omncomayo ekhasini azi ukuthi ufuna abone i-imeyili futhi akuwona ugaxekile.Ngeke sithwebule noma yimaphi amakheli e-imeyili.
Lo mbuzo usetshenziselwa ukuhlola ukuthi ingabe uyisivakashi futhi uvimbele ukuthunyelwa kogaxekile okuzenzakalelayo.
Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
Imephu ephelele yezinguquko ze-SARS-CoV-2 ezibalekela ingxube ye-Regeneron monoclonal antibody isiza ukuchaza ukuvela kwegciwane ekwelapheni iziguli.
Tyler N.Starr, Allison J.Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary (Manish C. Choudhary), Adam S. Dinges (Adam S.
Imephu ephelele yezinguquko ze-SARS-CoV-2 ezibalekela ingxube ye-Regeneron monoclonal antibody isiza ukuchaza ukuvela kwegciwane ekwelapheni iziguli.
©2021 Inhlangano YaseMelika Yokuthuthukiswa Kwesayensi.wonke Amalungelo Agodliwe.I-AAAS inguzakwethu we-HINARI, AGORA, OARE, CHORUS, CLOCKSS, CrossRef kanye ne-COUNTER.Science ISSN 1095-9203.
Isikhathi sokuthumela: Feb-24-2021