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We previously demonstrated that a cell\u2010permeable peptide corresponding to the severe acute respiratory syndrome coronavirus 2\u00a0(SARS\u2010CoV\u20102) Spike C\u2010terminal domain (CD)\u00a0inhibits the interaction between viral spike and nucleocapsid proteins that results in SARS\u2010CoV\u20102 replication in vitro. Here, we used docking studies to design R\u2010t\u2010Spike CD(D), a more potent short cell\u2010penetrating peptide composed of all D\u2010form amino acids and evaluated its inhibitory effect against the replication of SARS\u2010CoV\u20102 S clade and other variants. R\u2010t\u2010Spike CD(D) was internalized into Vero cells and Calu\u20103 cells and suppressed the replication of\u00a0SARS\u2010CoV\u20102 S clade, delta variant, and omicron variant with higher potency than the original peptide. In hemizygous K18\u2010hACE2 mice, intratracheal administration of R\u2010t\u2010Spike CD(D) effectively delivered the peptide to the trachea and lungs, whereas intranasal administration delivered the peptide mostly to the upper respiratory system and stomach, and a small amount to the lungs. Administration by either route reduced viral loads in mouse lungs and turbinates. Furthermore, intranasally administered R\u2010t\u2010Spike CD(D) mitigated pathological change in the lungs and increased the survival of mice after infection with the SARS\u2010CoV\u20102 S clade or delta variant. Our data suggest that R\u2010t\u2010Spike CD(D) has potential as a therapeutic agent against SARS\u2010CoV\u20102 infection.<\/jats:p>","DOI":"10.1002\/jmv.28626","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T11:37:49Z","timestamp":1677670669000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["In vitro and in vivo suppression of SARS\u2010CoV\u20102 replication by a modified, short, cell\u2010penetrating peptide targeting the C\u2010terminal domain of the viral spike protein"],"prefix":"10.1002","volume":"95","author":[{"given":"Dongbum","family":"Kim","sequence":"first","affiliation":[{"name":"Institute of Medical Science, College of Medicine Hallym University  Chuncheon South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Medicine Hallym 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