The Covid-19 NMR Consortium, an international collaboration of NMR experts, is conducting research to determine the ribonucleic acid (RNA) structure of SARS-CoV-2 and its proteins using NMR spectroscopy. One of the consortium’s first discoveries, early on in the pandemic, was that a protein within SARS-CoV-2 forms microdroplets with the RNA of the virus. In subsequent months, this discovery enabled scientists to set up experiments to study the interplay between the RNA and the protein, known as the nucleocapsid protein or N protein.

At the invitation of Prof. Schwalbe, Prof. Markus Zweckstetter joined the consortium in late 2020 after the publication of his research on SARS-CoV-2. As part of this 50-strong international collaboration of NMR experts, Prof. Zweckstetter and his team at the Max Planck Institute for Multidisciplinary Sciences in Göttingen, Germany, have been uncovering insights into the hidden workings of Covid-19. Using one of only a few 1.2 GHz NMR instruments in the world, these researchers are helping to elucidate the structure and interactions of the nucleocapsid protein within the SARS-CoV-2 virus and, in doing so, identify promising options for drug targets.

Mechanisms of Covid-19

The etiologic agent of the Covid-19 pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many early studies of SARS-CoV-2 focused on the so-called ‘spike protein’ because this is involved in communication with the host cell. But as an understanding of SARS-CoV-2 has evolved, it has become apparent that the nucleocapsid protein, or N protein, also plays a key role because it not only protects the RNA from degradation, but enables the transcription machinery to cluster, and so enhances its ability to replicate.

The viral membrane of SARS-CoV-2 surrounds a helical nucleocapsid in which the viral genome is encapsulated by the nucleocapsid protein. The nucleocapsid About the COVID-19 NMR Consortium The Covid-19 NMR Consortium was initiated at the Goethe University in Frankfurt, Germany, in March 2020 by Prof. Dr. Harald Schwalbe and it has since grown rapidly into an international consortium. Today, scientists from all over the world are collaborating based on open science principles in a unique effort to investigate SARS-CoV-2 using NMR spectroscopy. The goals and the shared scientific targets of the project are coordinated by Prof. Schwalbe and his team at Goethe University. The core team includes five professors and junior group leaders from Darmstadt and Frankfurt and nine senior scientists from the Biological Magnetic Resonance Center (BMRZ) in Frankfurt. The overall goal of this consortium is to join forces to achieve meaningful scientific results in Covid-19 research as quickly as possible. a protein of SARS-CoV-2 is produced at high levels within infected cells, enhances the efficiency of viral RNA transcription, and is essential for viral replication. Scientists at the German Center for Neurodegenerative Diseases (DZNE) and the Max Planck Institute have now shown that this protein and the RNA can jointly condense into tiny droplets when the virus releases its insides into a host cell. Continued research determined that RNA induces cooperative liquid-liquid phase separation of the SARS-CoV-2 nucleocapsid protein, where the viral droplets float inside the fluid medium inside the cell. However, this droplet formation is not a speciality of the coronavirus. Such dynamic compartments composed of proteins and other molecules occur naturally inside cells, and they are used as storage sites and reaction chambers. Research by Prof. Zweckstetter and his team shows that the coronavirus also exploits these possibilities, and this is suspected to happen with other pathogens as well. In agreement with its ability to phase separate in vitro, protein associates in cells with stress granules – cytoplasmic RNA/ protein granules that form through liquid-liquid phase separation and are modulated by viruses to maximize replication efficiency. This process generates high-density protein/ RNA condensates that recruit the RNA-dependent RNA polymerase complex of SARS-CoV-2, providing a mechanism for efficient transcription of viral RNA. Inhibition of RNA-induced phase separation of the nucleocapsid protein by small molecules or biologics thus can interfere with a key step in the SARS-CoV-2 replication cycle.¹