Abstract
Human coronavirus 229E (HCoV-229E) infection in infants, elderly people, and immunocompromised patients can cause severe disease, thus calling for the development of effective and safe therapeutics to treat it. Here we reported the design, synthesis and characterization of two peptide-based membrane fusion inhibitors targeting HCoV-229E spike protein heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains, 229E-HR1P and 229E-HR2P, respectively. We found that 229E-HR1P and 229E-HR2P could interact to form a stable six-helix bundle and inhibit HCoV-229E spike protein-mediated cell-cell fusion with IC50 of 5.7 and 0.3 µM, respectively. 229E-HR2P effectively inhibited pseudotyped and live HCoV-229E infection with IC50 of 0.5 and 1.7 µM, respectively. In a mouse model, 229E-HR2P administered intranasally could widely distribute in the upper and lower respiratory tracts and maintain its fusion-inhibitory activity. Therefore, 229E-HR2P is a promising candidate for further development as an antiviral agent for the treatment and prevention of HCoV-229E infection.
Highlights
Coronaviruses (CoVs) are positive-sense RNA enveloped viruses with various hosts, including avian species and mammals [1]
We found that 229E-HR1P and 229E-HR2P could effectively inhibit HCoV-229E infection and replication in Huh-7 cells in a dose-dependent manner with IC50
We found that 229E-HR1P and 229E-HR2P could effectively inhibit HCoV-229E ivnafleucetIinsot.onJ.fMa1no3l.d.2Scriμ.e2Mp01l8iac, 1na9td,io1n.9i6nμHMu,hr-e7spceeclltsivienlya,ncdoennstismteanntnweirthwtihtheiIrCin50hivbailtuoreys aocf7toi1vf31i.t42ieμsMin aiAasnn5add4h91rvAu.ec9ap5me6l4ulli9laμecsnscaM, etowrli,floeshr1ns,ei3pwcs.(2ihpFhrμeiaiigccstMhuotairrivasyehneau5ldeychmp1)u(i.aF9t[mh36nig0aeμrn]ul.Meirarseel,psr5ciperebsialr)plta,oetlccoriotnyrinyveeseeapilpsynititt(dehhFneeisgtlluiiuwaasrllceictcee5heplblltt)lhil,iblcneilnoeierneastinaonisdnhtHedisnbuCtsistuowcoesVirpcty-het2ipab2thtcl9eietEbiitvrloeiiintnHtifhoeeCiscbHotiiVintCoo-r2Anoy2V59aa4-Enc29tdi2invc9fireEteelicelpitssnil,oiifwcnneachttiiioconhn (Figuarend5cr)ep[3li0c]a.tion (Figure 5c) [30]
Summary
Coronaviruses (CoVs) are positive-sense RNA enveloped viruses with various hosts, including avian species and mammals [1]. TToo ffuurrtthheerrstsutuddyychcahraarcatcetreisrtiisctsicsofotfhethienteinratecrtiaocntiobnetwbeetewne2e2n9E2-2H9ER-1HPRa1nPd a2n2d9E-2H29RE2-PH, Rw2eP, dweetedrmetienremdintheedstehceonsdecaoryndstarruyctsutrruesctoufr2e2s9oEf-H22R91EP-H, 2R219PE,-H22R92EP-HanRd2Pthaenirdcothmepirlecxominpmleixxtiunrem(2ix2t9uEr-e H(2R291EP-/H22R91EP-H/2R229PE)-HbyR2cPir)cbuylacri-rdciuclharro-disimchr(oCisDm) s(CpeDc)trsopseccotproys.cAopsys.hAoswsnhoiwn nFiignuFrieg2ucr,e222c9, E22-H9ER-1HPRo1rP 2o2r9E2-2H9ER-2HPRa2lPonaelodnisepldaiysepdlayaedrelaatirveellaytivloewly αlo-hweliαci-thyelsictriutyctustrreu, cwtuhreer, eawshtehreeams itxhteurme ioxftu2r2e9Eo-f H22R91EP-/H22R91EP-/H2R229PE-HatR2ePquaitmoeqlaurimcoolnacrenctornatcieonntrasthioonwesdhoawecdomapcleoxmpwleitxh whiitghh hαig-hhelαic-ihteyl,iciatsy, cahsarcahcatrearcizteerdizbeydthbye stahdedslaed-sdhlaep-sehdanpeegdatnievgeaptievaek patea2k08aatn2d0822a2nndm22in tnhme fianr tUhVe fraergiUonVorfetghieonCDof spectrum This helical bundle showed strong thermal stability with a Tm of 90.1 °C (Figure 2d), which is higher than that of the MERS-CoV HR1P/HR2P complex (~87 °C). Matsuyama et al have reported that the current clinical isolates of HCoV-229E preferably use TMPRSS2, rather than CPL, to infect epithelial cells in the human respiratory tract [14], suggesting that HCoV-229E-specific fusion inhibitory peptides are expected to inhibit membrane fusion mediated by HCoV-229E S protein that is proteolytically processed by TMPRSS2. 229E-HR2P is able to maintain its fusion-inhibitory activity in both upper and lower respiratory tracts, suggesting its promise as a candidate for development into an effective and safe HCoV-229E fusion inhibitor for prevention and treatment of HCoV-229E infection
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