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Recent:   

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

Mäkelä et al., Nature Communications, doi:10.1038/s41467-023-37290-6
Mar 2023  
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In Vitro and mouse study showing that TriSb92, a trimeric antibody-mimetic sherpabody, potently neutralizes SARS-CoV-2 variants including recent Omicron subvariants. Authors found that TriSb92 targets a highly conserved region in the receptor binding domain (RBD) of the spike protein, inhibiting infection with IC50 values in the picomolar to low nanomolar range for all tested variants. Cryo-EM analysis revealed that TriSb92 binding induces conformational changes in the spike protein, preventing viral entry without interfering with ACE2 binding. In mice, intranasal administration of TriSb92 provided both prophylactic and early therapeutic protection against SARS-CoV-2 infection, significantly reducing viral loads and preventing weight loss even with a lethal challenge dose. The compound showed high stability and no toxicity in human nasal epithelial cells, suggesting potential for development as an intranasal spray for COVID-19 prevention. TriSb92 also neutralized SARS-CoV-1, indicating possible broad protection against sarbecoviruses.
Mäkelä et al., 24 Mar 2023, peer-reviewed, 23 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Abstract: Article https://doi.org/10.1038/s41467-023-37290-6 Intranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants Received: 22 December 2022 Check for updates 1234567890():,; 1234567890():,; Accepted: 10 March 2023 Anna R. Mäkelä1, Hasan Uğurlu 1, Liina Hannula2, Ravi Kant 1,3, Petja Salminen1, Riku Fagerlund1, Sanna Mäki1, Anu Haveri 4, Tomas Strandin1, Lauri Kareinen1,3, Jussi Hepojoki 1, Suvi Kuivanen1, Lev Levanov1, Arja Pasternack 5, Rauno A. Naves5, Olli Ritvos5, Pamela Österlund 4, Tarja Sironen 1,3, Olli Vapalahti 1,3,6, Anja Kipar 3,7, Juha T. Huiskonen 2, Ilona Rissanen 2 & Kalle Saksela 1,6 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. The success of the current vaccines in the fight against the SARS-CoV-2 pandemic is challenged by the emergence of viral variants of concern (VOCs) that show strong resistance to neutralizing antibodies induced by vaccinations or prior infection. Moreover, immune disorders or other health conditions can preclude appropriate vaccine responses in many individuals. In addition to pharmaceuticals for treating COVID-19 disease, new approaches for preventing transmission and spreading of SARS-CoV-2 are therefore urgently needed. Since the nasal epithelium of the respiratory tract is the first dominant replication site of SARS-CoV-2 preceding virus transport into the lung1, intranasal administration of SARS-CoV-2 neutralizing agents poses an attractive prophylactic concept. In animal models, 1 Department of Virology, University of Helsinki, Helsinki, Finland. 2Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Helsinki, Finland. 3Department of Basic Veterinary Sciences, University of Helsinki, Helsinki, Finland. 4Finnish Institute for Health and Welfare, Helsinki, Finland. 5 Department of Physiology, University of Helsinki, Helsinki, Finland. 6HUS Diagnostic Centre, HUSLAB, Clinical Microbiology, Helsinki University Hospital, Helsinki, Finland. 7Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. e-mail: kalle.saksela@helsinki.fi Nature Communications | (2023)14:1637 1 Article https://doi.org/10.1038/s41467-023-37290-6 monoclonal antibodies..
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Biol.'}, { 'key': '37290_CR44', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-020-19204-y', 'volume': '11', 'author': 'TF Custodio', 'year': '2020', 'unstructured': 'Custodio, T. F. et al. Selection, biophysical and structural analysis of ' 'synthetic nanobodies that effectively neutralize SARS-CoV-2. Nat. ' 'Commun. 11, 5588 (2020).', 'journal-title': 'Nat. Commun.'}, { 'key': '37290_CR45', 'doi-asserted-by': 'publisher', 'first-page': '70', 'DOI': '10.1002/pro.3943', 'volume': '30', 'author': 'EF Pettersen', 'year': '2021', 'unstructured': 'Pettersen, E. F. et al. UCSF ChimeraX: Structure visualization for ' 'researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).', 'journal-title': 'Protein Sci.'}, { 'key': '37290_CR46', 'doi-asserted-by': 'publisher', 'first-page': '2126', 'DOI': '10.1107/S0907444904019158', 'volume': '60', 'author': 'P Emsley', 'year': '2004', 'unstructured': 'Emsley, P. & Cowtan, K. Coot: Model-building tools for molecular ' 'graphics. 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Biol.'}, { 'key': '37290_CR49', 'doi-asserted-by': 'publisher', 'first-page': '934', 'DOI': '10.1038/s41594-020-0478-5', 'volume': '27', 'author': 'X Xiong', 'year': '2020', 'unstructured': 'Xiong, X. et al. A thermostable, closed SARS-CoV-2 spike protein trimer. ' 'Nat. Struct. Mol. Biol. 27, 934–941 (2020).', 'journal-title': 'Nat. Struct. Mol. Biol.'}], 'container-title': 'Nature Communications', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s41467-023-37290-6.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41467-023-37290-6', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41467-023-37290-6.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 3, 24]], 'date-time': '2023-03-24T11:05:58Z', 'timestamp': 1679655958000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41467-023-37290-6'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 3, 24]]}, 'references-count': 49, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2023, 12]]}}, 'alternative-id': ['37290'], 'URL': 'http://dx.doi.org/10.1038/s41467-023-37290-6', 'relation': {}, 'ISSN': ['2041-1723'], 'subject': [ 'General Physics and Astronomy', 'General Biochemistry, Genetics and Molecular Biology', 'General Chemistry', 'Multidisciplinary'], 'container-title-short': 'Nat Commun', 'published': {'date-parts': [[2023, 3, 24]]}, 'assertion': [ { 'value': '22 December 2022', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '10 March 2023', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '24 March 2023', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { '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.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '1637'}
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