LEE KRAMER'S ROOM: With Views

[jbsliverer]

Looks promising. The spray targets an area of the spike that is conserved (doesn't mutate) so that the region "changes its shape". This change prevents attachment of the virus to the host cell. 🤞🤞 https://t.co/YKfVhaNWFw

— Jette is Mataray 😊 (@white_bite) March 25, 2023

https://www.nature.com/articles/s41467-023-37290-6
Abstract
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.

Introduction
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, monoclonal antibodies targeted against the spike envelope protein of SARS-CoV-2 have shown to be effective for COVID-19 prophylaxis2,3,4,5,6. To avoid mutational escape from neutralization, such antibodies have been used as cocktails and targeted against conserved regions of spike7. Markedly increased potency could also be achieved by constructing a pentameric IgM version of spike-targeted IgG antibodies4.

To develop more economical and manufacturable anti-SARS-CoV-2 reagents, many laboratories have moved from monoclonal antibodies to smaller antibody fragments, including single variable domain-based nanobodies. Several of these have shown promising antiviral efficacy in cell culture or animal models, including utility as an intranasal SARS-CoV-2 prophylaxis8,9,10,11.

Compared to these, small antibody-mimetic scaffold proteins are even more robust, versatile to engineer, and cheaper to produce for diverse biological targeting purposes12. Sherpabodies (SH3 Recombinant Protein Affinity) are very small (<?60 aa) targeting modules that constitute a recent addition to the toolbox of scaffold targeting proteins and comprise of an improved SH3-domain fold derived from the human ciliary adaptor protein nephrocystin13. Here, we report engineering of a sherpabody targeted against a highly conserved region in the spike receptor binding domain (RBD) into a potent prophylactic anti-SARS-CoV-2 agent.