Abstract
The prolonged duration of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has resulted in the continuous emergence of variants of concern (VOC, e.g., Omicron) and variants of interest (VOI, e.g., Lambda). These variants have challenged the protective efficacy of current COVID-19 vaccines, thus calling for the development of novel therapeutics against SARS-CoV-2 and its VOCs. Here, we constructed a novel fusion inhibitor-based recombinant protein, denoted as 5-Helix, consisting of three heptad repeat 1 (HR1) and two heptad repeat 2 (HR2) fragments. The 5-Helix interacted with the HR2 domain of the viral S2 subunit, the most conserved region in spike (S) protein, to block homologous six-helix bundle (6-HB) formation between viral HR1 and HR2 domains and, hence, viral S-mediated cell–cell fusion. The 5-Helix potently inhibited infection by pseudotyped SARS-CoV-2 and its VOCs, including Delta and Omicron variants. The 5-Helix also inhibited infection by authentic SARS-CoV-2 wild-type (nCoV-SH01) strain and its Delta variant. Collectively, our findings suggest that 5-Helix can be further developed as either a therapeutic or prophylactic to treat and prevent infection by SARS-CoV-2 and its variants.
Highlights
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has posed an unprecedented threat to public health, with over 5.67 million deaths and 370 million confirmed diseases through 29 January 2021
We found that 5-Helix could interact with the SARS-CoV-2 heptad repeat 2 (HR2) peptide to form 6-HB, potently inhibiting 6-HB formation between heptad repeat 1 (HR1) and HR2 of SARS-CoV-2 and, S-mediated cell–cell fusion and infection by SARS-CoV-2 and its variants of concern, including the recently emerged Omicron
We designed and constructed a 5-Helix fusion protein consisting of three copies of HR1P (a 44-mer peptide corresponding to residues L922~Q965 of HR1 in S2 of SARS-CoV-2) and two copies of HR2P
Summary
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has posed an unprecedented threat to public health, with over 5.67 million deaths and 370 million confirmed diseases through 29 January 2021 (https://covid19.who.int/, accessed on 29 January 2021). The continuing worldwide spread and transmission of SARS-CoV-2 have resulted in the emergence of many variants of concern (VOC) and interest (VOI), as defined by WHO (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/, accessed on 29 January 2021). The newly emerged VOC Omicron (B.1.1.529), which contains 32 mutations within its S protein, has exhibited significantly increased resistance to the neutralizing antibodies elicited by the current COVID-19 vaccines and therapeutics [2,3], Viruses 2022, 14, 597. Viruses 2022, 14, 597 Viruses 2022, 14, 597 the neutralizing antibodies elicited by the current COVID−19 vaccines and therapeutics [2,3], calling for the development of more effective and broader−spectrum antivirals agatihnuststchaellsiengVOfoCr sthaenddeVveOloIsp.ment of more effective and broader-spectrum antivirals against thTehsee VfuOnCctsioannadl VdoOmIsa.ins, known as heptad repeat 1 (HR1) and 2 (HR2) in the S2 subunit of thTeheSAfuRnSc−tiConoaVl−d2osmpaikines(,Sk)nporwotneians,hpelpaytacdrirteipcaelarto1le(Hs iRn1f)oarnmdi2ng(HthRe2)siixn−thheeliSx2bsuunb-unit dleo(f6−thHeBS) AfuRsSio-CnocVo-r2e s(Fpiigkuer(eS1) Ap,rBo)teainnd, pmlaeydicartiitnicgalvriroallesfuisniofnoramnidngenthtrey siinxt-ohethliex hbousntdle cell(.6H-HRB1)afnudsioHnRc2oarels(oFhigauvreet1hAe ,mB)oasnt dcomnseedrivaetdingsevqiureanl cfuessiionnSanpdroetenitnr.yCinotnosethqeuehnotslyt ,cell. Hfuoswionevienrh,ibniotory pepptiedpetitdaergs,etsiuncghHaRs2EoKf 1th[e5S],AHRRS−2CPo[V6]−,2ESKp1rCo4te[in7]haansdbeEeKnLre1pCor[t8e]d. sHoofware, veveer,nntohopuegphtide HRt2arhgaestiangmHorRe2coofnstherevSeAdRsSeq-CuoenVc-2e SthparnoHteiRn1h(aFsigbuereenSr1e)p[o6r]t.ePdresvoifoaurs, esvtuenditehsoounghthHe R2 pephtiadseas mdeorrievceodnfsreormvedthseeqHuIeVn−c1e tghpa4n1HNRH1R(FiagnudreCSH1)R[6(]a.lsPorekvnioouwsnstausdHiesRo1natnhde HpeRp2ti)des pepdtiedrievsehdafvreomdetmheonHsItVra-1tegdpt4h1aNt NHHRRanpdepCtHidRes(,aslsuochknaoswNn3a6s, eHxRh1ibaitnadnHtivRi2r)apl aepcttiivdietys h2ave to 3doemrdoenrsstlroawteedrtthhaatnNtHhaRt poefpCtiHdRes,pseupcthidaess,Ns3u6c,hexahsiCbi3t4a.nCtiovmiraplaarcetdivtiotya2CtoH3Roprdepertsidloe,wer an NthHanRtpheapt toifdCe HgeRnepreaplltyidceosn, tsauinchs amsoCre34h.yCdorompphailriecdamtoianoCaHcRidspetoptfiodrem, aNn HNRH−Rtripmepertide witghetnheeraclolynccoomntiatiannstmpororephenysdirtoypthoilaicggamreignaoteacinidps htoyfsoiormlogNicHalRs-torliumtieornws i[t9h].thEexctroanpcoolmati-tant ingp, irtopiseennsittiyretloy apgogsrseigbaletethinatppheypsitoidloegsicdaelrsivoeludtifornosm[9t]h.eESxAtrRapSo−lCaotiVng−,2itHisRe1ndtiormelyaipno[s6s]ible that peptides derived from the SARS-CoV-2 HR1 domain [6] may behave in a manner maysimbeihlaarvteoitnhaatmoaf nHnIeVr-1simgpi4la1rNtoHtRhapteopftHidIeVs−[19,g1p0]4.1 NHR peptides [9,10]
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