TY - JOUR T1 - Intranasal inhibitor blocks Omicron and other variants of SARS-CoV-2 JF - bioRxiv DO - 10.1101/2021.12.28.474326 SP - 2021.12.28.474326 AU - Anna R. Mäkelä AU - Hasan Uğurlu AU - Liina Hannula AU - Petja Salminen AU - Ravi Kant AU - Riku Fagerlund AU - Anu Haveri AU - Tomas Strandin AU - Lauri Kareinen AU - Jussi Hepojoki AU - Lev Levanov AU - Arja Pasternack AU - Rauno A. Naves AU - Olli Ritvos AU - Pamela Österlund AU - Tarja Sironen AU - Olli Vapalahti AU - Anja Kipar AU - Juha T. Huiskonen AU - Ilona Rissanen AU - Kalle Saksela Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/12/28/2021.12.28.474326.abstract N2 - The emergence of the SARS-CoV-2 Omicron variant capable of escaping neutralizing antibodies emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Nasal epithelium is rich in the ACE2 receptor and important for SARS-CoV-2 transmission by supporting early viral replication before seeding to the lung1. Intranasal administration of SARS-CoV-2 neutralizing antibodies or antibody fragments has shown encouraging potential as a protective measure in animal models2-5. However, there remains a need for SARS-CoV-2 blocking agents that are more economical to produce in large scale, while less vulnerable to mutational variation in the neutralization epitopes of the viral Spike glycoprotein. Here we describe TriSb92, a highly manufacturable trimeric human nephrocystin SH3 domain-derived antibody mimetic targeted against a conserved region in the receptor-binding domain of the Spike. TriSb92 potently neutralizes SARS-CoV-2 and its variants of concern, including Delta and Omicron. Intranasal administration of a modest dose of TriSb92 (5 or 50 micrograms) as early as eight hours before the challenge with SARS-CoV-2 B.1.351 efficiently protected mice from infection. The target epitope of TriSb92 was defined by cryo-EM, which revealed triggering of a conformational shift in the Spike trimer rather than competition for ACE2 binding as the molecular basis of its strong inhibitory action. Our results highlight the potential of intranasal inhibitors in protecting susceptible individuals from SARS-CoV-2 infection, and describe a novel type of inhibitor that could be of use in addressing the challenge posed by the Omicron variant.Competing Interest StatementKS is founder and shareholder of Next Biomed Therapies Oy that develops SH3 scaffold targeting technologies ARM is founder and shareholder of a start-up that has acquired commercial rights for TriSb92 ER -