Abstract
The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is the most severe public health event of the twenty-first century. While effective vaccines against SARS-CoV-2 have been developed, there remains an urgent need for diagnostics to quickly and accurately detect infections. Antigen tests, particularly those that detect the abundant SARS-CoV-2 Nucleocapsid protein, are a proven method for detecting active SARS-CoV-2 infections. Here we report high-resolution crystal structures of three llama-derived single-domain antibodies that bind the SARS-CoV-2 Nucleocapsid protein with high affinity. Each antibody recognizes a specific folded domain of the protein, with two antibodies recognizing the N-terminal RNA binding domain and one recognizing the C-terminal dimerization domain. The two antibodies that recognize the RNA binding domain affect both RNA binding affinity and RNA-mediated phase separation of the Nucleocapsid protein. All three antibodies recognize highly conserved surfaces on the Nucleocapsid protein, suggesting that they could be used to develop affordable diagnostic tests to detect all circulating SARS-CoV-2 variants.
Highlights
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has resulted in over 170 million confirmed cases and caused over 3.5 million deaths as of early June 2021 (John Hopkins Coronavirus Resource Center, https://coronavirus.jhu.edu)
Two recent studies reported the isolation of single-domain antibodies that recognize the SARS-CoV-2 N protein (Figures 1A, B) [18, 19]
The SARS-CoV-2 N protein possesses a modular structure with an N-terminal RNA-binding domain (RBD) and a Cterminal dimerization domain (CTD), plus three intrinsically disordered regions at the N- and C-termini (N-IDR and C-IDR, respectively) and in the serine/arginine region separating the RBD and C-terminal dimerization domain (CTD) (SR-IDR; Figure 1A)
Summary
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has resulted in over 170 million confirmed cases and caused over 3.5 million deaths as of early June 2021 (John Hopkins Coronavirus Resource Center, https://coronavirus.jhu.edu). In order to detect and quickly respond to new infections and local outbreaks, robust diagnostic tools are required that can quickly and reliably detect active SARS-CoV-2 infections. Antigen tests are immunoassays that detect the presence of a viral antigen such as an abundant protein, and constitute an effective means of detecting active infections for respiratory pathogens including SARS and SARS-CoV-2 [4,5,6]. Antigen tests are an important complement to PCR-based tests, which detect the presence of viral nucleic acids (genomic or subgenomic RNA in the case of SARS-CoV-2), but may give positive results after a patient is no longer infectious. While antigen tests are less sensitive than PCR-based tests, they are generally faster and require less specialized equipment than PCR tests, enabling wider deployment than PCR-based tests
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