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TitleIntranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 1637, Year 2023
Publish dateMar 24, 2023
AuthorsAnna R Mäkelä / Hasan Uğurlu / Liina Hannula / Ravi Kant / Petja Salminen / Riku Fagerlund / Sanna Mäki / Anu Haveri / Tomas Strandin / Lauri Kareinen / Jussi Hepojoki / Suvi Kuivanen / Lev Levanov / Arja Pasternack / Rauno A Naves / Olli Ritvos / Pamela Österlund / Tarja Sironen / Olli Vapalahti / Anja Kipar / Juha T Huiskonen / Ilona Rissanen / Kalle Saksela /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:36964125 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.1 Å
Structure data

16383

8c1v

EMDB-16383: Cryo-EM map of SARS-CoV-2 S-trimer (3 RBDs up) in complex with neutralizing sherpabody TriSb92
PDB-8c1v: SARS-CoV-2 S-trimer (3 RBDs up) bound to TriSb92, fitted into cryo-EM map
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-16388: CryoEM density of SARS-CoV-2 S spike (3 RBDs down)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL PROTEIN / SARS-CoV-2 spike / sherpabody / coronavirus

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