The COVID-19 (Coronavirus disease-2019) pandemic, caused by the SARS-CoV-2 coronavirus, is a significant threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and MERS-CoV. Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analysis for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 Orf9b, an interaction we structurally characterized using cryo-EM. Combining genetically-validated host factors with both COVID-19 patient genetic data and medical billing records identified important molecular mechanisms and potential drug treatments that merit further molecular and clinical study.
The SARS-CoV-2 virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryogenic electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.
The National High Magnetic Field Laboratory has brought to field a Series-Connected Hybrid magnet for NMR spectroscopy. As a DC powered magnet it can be operated at fields up to 36.1 T. The series connection between a superconducting outsert and a resistive insert dramatically minimizes the high frequency fluctuations of the magnetic field typically observed in purely resistive magnets. Current-density-grading among various resistive coils was used for improved field homogeneity. The 48 mm magnet bore and 42 mm outer diameter of the probes leaves limited space for conventional shims and consequently a combination of resistive and ferromagnetic shims are used. Field maps corrected for field instabilities were obtained and shimming achieved better than 1 ppm homogeneity over a cylindrical volume of 1 cm diameter and height. The magnetic field is regulated within 0.2 ppm using an external 7Li lock sample doped with paramagnetic MnCl2. The improved field homogeneity and field regulation using a modified AVANCE NEO console enables NMR spectroscopy at 1H frequencies of 1.0, 1.2 and 1.5 GHz. NMR at 1.5 GHz reflects a 50% increase in field strength above the highest superconducting magnets available presently. Three NMR probes have been constructed each equipped with an external lock rf coil for field regulation. Initial NMR results obtained from the SCH magnet using these probes illustrate the very exciting potential of ultra-high magnetic fields.
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