Intranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants

DOI record: { "DOI": "10.1038/s41467-023-37290-6", "ISSN": [ "2041-1723" ], "URL": "http://dx.doi.org/10.1038/s41467-023-37290-6", "abstract": "<jats:title>Abstract</jats:title><jats:p>The emergence of increasingly immunoevasive SARS-CoV-2 variants emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Intranasal administration of neutralizing antibodies has shown encouraging protective potential but there remains a need for SARS-CoV-2 blocking agents that are less vulnerable to mutational viral variation and more economical to produce in large scale. Here we describe TriSb92, a highly manufacturable and stable trimeric antibody-mimetic sherpabody targeted against a conserved region of the viral spike glycoprotein. TriSb92 potently neutralizes SARS-CoV-2, including the latest Omicron variants like BF.7, XBB, and BQ.1.1. In female Balb/c mice intranasal administration of just 5 or 50 micrograms of TriSb92 as early as 8 h before but also 4 h after SARS-CoV-2 challenge can protect from infection. Cryo-EM and biochemical studies reveal triggering of a conformational shift in the spike trimer as the inhibitory mechanism of TriSb92. The potency and robust biochemical properties of TriSb92 together with its resistance against viral sequence evolution suggest that TriSb92 could be useful as a nasal spray for protecting susceptible individuals from SARS-CoV-2 infection.</jats:p>", "alternative-id": [ "37290" ], "article-number": "1637", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "22 December 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "10 March 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "24 March 2023" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "K.S. is a founder and shareholder of Next Biomed Therapies Oy that develops SH3 scaffold targeting technologies. ARM is a founder and shareholder of the start-up Pandemblock Oy that has acquired commercial rights for TriSb92. The authors are inventors of the related patents/applications WO2017009533 (K.S.) and PCT/FI2022/050764 (K.S. and A.R.M.). The other authors have no competing interests to declare." } ], "author": [ { "affiliation": [], "family": "Mäkelä", "given": "Anna R.", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0002-3849-7847", "affiliation": [], "authenticated-orcid": false, "family": "Uğurlu", "given": "Hasan", "sequence": "additional" }, { "affiliation": [], "family": "Hannula", "given": "Liina", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-3878-9775", "affiliation": [], "authenticated-orcid": false, "family": "Kant", "given": "Ravi", "sequence": "additional" }, { "affiliation": [], "family": "Salminen", "given": "Petja", "sequence": "additional" }, { "affiliation": [], "family": "Fagerlund", "given": "Riku", "sequence": "additional" }, { "affiliation": [], "family": "Mäki", "given": "Sanna", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-4620-7536", "affiliation": [], "authenticated-orcid": false, "family": "Haveri", "given": "Anu", "sequence": "additional" 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