Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
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99 GENERAL AND MISCELLANEOUS↗
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A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2
The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2–3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.
59 BASIC BIOLOGICAL SCIENCES↗
A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody
Epitopes that are conserved among SARS-like coronaviruses are attractive targets for design of cross-reactive vaccines and therapeutics. CR3022 is a SARS-CoV neutralizing antibody to a highly conserved epitope on the receptor binding domain (RBD) on the spike protein that is able to cross-react with SARS-CoV-2, but with lower affinity. Using x-ray crystallography, mutagenesis, and binding experiments, we illustrate that of four amino acid differences in the CR3022 epitope between SARS-CoV-2 and SARS-CoV, a single mutation P384A fully determines the affinity difference. CR3022 does not neutralize SARS-CoV-2, but the increased affinity to SARS-CoV-2 P384A mutant now enables neutralization with a similar potency to SARS-CoV. We further investigated CR3022 interaction with the SARS-CoV spike protein by negative-stain EM and cryo-EM. Three CR3022 Fabs bind per trimer with the RBD observed in different up-conformations due to considerable flexibility of the RBD. In one of these conformations, quaternary interactions are made by CR3022 to the N-terminal domain (NTD) of an adjacent subunit. Overall, this study provides insights into antigenic variation and potential cross-neutralizing epitopes on SARS-like viruses.
59 BASIC BIOLOGICAL SCIENCES↗
Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2
Targeting the main protease of SARS-CoV-2 Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al . identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice.
Drayman, Nir↗
A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection
Coronaviruses have caused several human epidemics and pandemics including the ongoing coronavirus disease 2019 (COVID-19). Prophylactic vaccines and therapeutic antibodies have already shown striking effectiveness against COVID-19. Nevertheless, concerns remain about antigenic drift in SARS-CoV-2 as well as threats from other sarbecoviruses. Cross-neutralizing antibodies to SARS-related viruses provide opportunities to address such concerns. Here, we report on crystal structures of a cross-neutralizing antibody, CV38-142, in complex with the receptor-binding domains from SARS-CoV-2 and SARS-CoV. Recognition of the N343 glycosylation site and water-mediated interactions facilitate cross-reactivity of CV38-142 to SARS-related viruses, allowing the antibody to accommodate antigenic variation in these viruses. CV38-142 synergizes with other cross-neutralizing antibodies, notably COVA1-16, to enhance neutralization of SARS-CoV and SARS-CoV-2, including circulating variants of concern B.1.1.7 and B.1.351. Overall, this study provides valuable information for vaccine and therapeutic design to address current and future antigenic drift in SARS-CoV-2 and to protect against zoonotic SARS-related coronaviruses.
3D structure↗
Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors
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99 GENERAL AND MISCELLANEOUS↗
Potential pathogenicity determinants identified from structural proteomics of SARS-CoV and SARS-CoV-2
Despite SARS-CoV and SARS-CoV-2 being equipped with highly similar protein arsenals, the corresponding zoonoses have spread among humans at extremely different rates. The specific characteristics of these viruses that led to such distinct outcomes remain unclear. Here, we apply proteome-wide comparative structural analysis aiming to identify the unique molecular elements in the SARS-CoV-2 proteome that may explain the differing consequences. By combining protein modeling and molecular dynamics simulations, we suggest non-conservative substitutions in functional regions of the spike glycoprotein (S), nsp1, and nsp3 that are contributing to differences in virulence. Particularly, we explain why the substitutions at the receptor-binding domain of S affect the structure-dynamics behavior in complexes with putative host receptors. Conservation of functional protein regions within the two taxa is also noteworthy. We suggest that the highly conserved main protease, nsp5, of SARS-CoV and SARS-CoV-2 is part of their mechanism of circumventing the host interferon antiviral response. Overall, most substitutions occur on the protein surfaces and may be modulating their antigenic properties and interactions with other macromolecules. Our results imply that the striking difference in the pervasiveness of SARS-CoV-2 and SARS-CoV among humans seems to significantly derive from molecular features that modulate the efficiency of viral particles in entering the host cells and blocking the host immune response.
59 BASIC BIOLOGICAL SCIENCES↗
Broadening a SARS-CoV-1–neutralizing antibody for potent SARS-CoV-2 neutralization through directed evolution
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for strategies to rapidly develop neutralizing monoclonal antibodies that can function as prophylactic and therapeutic agents and to help guide vaccine design. Here, we demonstrate that engineering approaches can be used to refocus an existing antibody that neutralizes one virus but not a related virus. Through a rapid affinity maturation strategy, we engineered CR3022, a SARS-CoV-1–neutralizing antibody, to bind to the receptor binding domain of SARS-CoV-2 with >1000-fold increased affinity. The engineered CR3022 neutralized SARS-CoV-2 and provided prophylactic protection from viral challenge in a small animal model of SARS-CoV-2 infection. Deep sequencing throughout the engineering process paired with crystallographic analysis of engineered CR3022 elucidated the molecular mechanisms by which the antibody can accommodate sequence differences in the epitopes between SARS-CoV-1 and SARS-CoV-2. This workflow provides a blueprint for the rapid broadening of neutralization of an antibody from one virus to closely related but resistant viruses.
Biochemistry & Molecular Biology↗
Structure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease
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99 GENERAL AND MISCELLANEOUS↗
Earth observing SAR data processing systems at the Jet Propulsion Laboratory - Seasat to EOS SAR
The evolution of SAR digital data processing and management ground systems developed at the JPL for earth science missions is discussed. Attention is given to the SAR ground data system requirements, the early data processing systems, the Seasat SAR system, and the SIR-B data processing system. Special consideration is given to two currently operational SAR data systems: the JPL aircraft SAR processing system that flies on the NASA DC-8 and the Alaska SAR Facility at Fairbanks.
Nichols, David A.↗
Feasibility of sea ice typing with synthetic aperture radar (SAR): Merging of Landsat thematic mapper and ERS 1 SAR satellite imagery
Earth Remote-Sensing Satellite (ERS) 1 synthetic aperture radar (SAR) and Landsat thematic mapper (TM) images were acquired for the same area in the Beaufort Sea, April 16 and 18, 1992. The two image pairs were colocated to the same grid (25-m resolution), and a supervised ice type classification was performed on the TM images in order to classify ice free, nilas, gray ice, gray-white ice, thin first-year ice, medium and thick first-year ice, and old ice. Comparison of the collocated SAR pixels showed that ice-free areas can only be classified under calm wind conditions (less than 3 m/s) and for surface winds greater than 10 m/s based on the backscattering coefficient alone. This is true for pack ice regions during the cold months of the year where ice-free areas are spatially limited and where the capillary waves that cause SAR backscatter are dampened by entrained ice crystals. For nilas, two distinct backscatter classes were found at -17 dB and at -10 dB. The higher backscattering coefficient is attributed to the presence of frost flowers on light nilas. Gray and gray-white ice have a backscatter signature similar to first-year ice and therefore cannot be distinguished by SAR alone. First-year and old ice can be clearly separated based on their backscattering coefficient. The performance of the Geophysical Processor System ice classifier was tested against the Landsat derived ice products. It was found that smooth first-year ice and rough first-year ice were not significantly different in the backscatter domain. Ice concentration estimates based on ERS 1 C band SAR showed an error range of 5 to 8% for high ice concentration regions, mainly due to misclassified ice-free and smooth first-year ice areas. This error is expected to increase for areas of lower ice concentration. The combination of C band SAR and TM channels 2, 4, and 6 resulted in ice typing performance with an estimated accuracy of 90% for all seven ice classes.
Steffen, Konrad↗
The response of SAR imagery to azimuth travelling ocean surface waves as determined from shuttle SAR imagery
Comparisons between two-dimensional ocean wave spectra, derived from synthetic aperture radar (SAR) imagery, and two-dimensional wave spectra from independent instruments have shown good agreement. The procedure by which raw SAR image intensity-variance spectra are converted to estimates of wave spectra is dependent upon models of how a SAR is able to image ocean waves. The greatest uncertainty exists about the mechanism by which azimuth (along track) traveling waves are imaged. In this paper, independent wave spectra from an airborne, radar ocean wave spectrometer (ROWS) are systematically compared with spatially and temporally coincident shuttle SAR image intensity-variance spectra to determine an optimum description of the relationship between the two. The result of these comparisons is to demonstrate that a SAR image intensity-variance spectrum is nearly proportional to the ocean wave slope-variance spectrum for azimuth traveling waves.
Monaldo, Frank M.↗
Comprehensive characterization of N- and O- glycosylation of SARS-CoV-2 human receptor angiotensin converting enzyme 2
The emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created the need for development of new therapeutic strategies. Understanding the mode of viral attachment, entry and replication has become a key aspect of such interventions. The coronavirus surface features a trimeric spike (S) protein that is essential for viral attachment, entry and membrane fusion. The S protein of SARS-CoV-2 binds to human angiotensin converting enzyme 2 (hACE2) for entry. Herein, we describe glycomic and glycoproteomic analysis of hACE2 expressed in HEK293 cells. We observed high glycan occupancy (73.2 to 100%) at all seven possible N-glycosylation sites and surprisingly detected one novel O-glycosylation site. To deduce the detailed structure of glycan epitopes on hACE2 that may be involved in viral binding, we have characterized the terminal sialic acid linkages, the presence of bisecting GlcNAc and the pattern of N-glycan fucosylation. We have conducted extensive manual interpretation of each glycopeptide and glycan spectrum, in addition to using bioinformatics tools to validate the hACE2 glycosylation. Our elucidation of the site-specific glycosylation and its terminal orientations on the hACE2 receptor, along with the modeling of hACE2 glycosylation sites can aid in understanding the intriguing virus-receptor interactions and assist in the development of novel therapeutics to prevent viral entry. Here, the relevance of studying the role of ACE2 is further increased due to some recent reports about the varying ACE2 dependent complications with regard to age, sex, race and pre-existing conditions of COVID-19 patients.
59 BASIC BIOLOGICAL SCIENCES↗
Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge
Ever-evolving SARS-CoV-2 variants of concern (VOCs) have diminished the effectiveness of therapeutic antibodies and vaccines. Developing a coronavirus vaccine that offers a greater breadth of protection against current and future VOCs would eliminate the need to reformulate COVID-19 vaccines. Here, we rationally engineer the sequence-conserved S2 subunit of the SARS-CoV-2 spike protein and characterize the resulting S2-only antigens. Structural studies demonstrate that the introduction of interprotomer disulfide bonds can lock S2 in prefusion trimers, although the apex samples a continuum of conformations between open and closed states. Immunization with prefusion-stabilized S2 constructs elicits broadly neutralizing responses against several sarbecoviruses and protects female BALB/c mice from mouse-adapted SARS-CoV-2 lethal challenge and partially protects female BALB/c mice from mouse-adapted SARS-CoV lethal challenge. These engineering and immunogenicity results should inform the development of next-generation pan-coronavirus therapeutics and vaccines.
60 APPLIED LIFE SCIENCES↗
Mathematical modeling and SAR simulation multifunction SAR technology efforts
The orbital SAR (synthetic aperture radar) simulation data was used in several simulation efforts directed toward advanced SAR development. Efforts toward simulating an operational radar, simulation of antenna polarization effects, and simulation of SAR images at serveral different wavelengths are discussed. Avenues for improvements in the orbital SAR simulation and its application to the development of advanced digital radar data processing schemes are indicated.
Griffin, C. R.↗
Calibration Results for J-ERS-1 SAR Data Produced by the Alaska SAR Facility
The Alaska SAR Facility has been receiving and processing SAR data from the J-ERS-1 satellite since Spring 1992. Corner reflectors have been set up for J-ERS-1 SAR calibration at a site near Delta Junction, in central Alaska. Image quality and calibration analysis results from the Delta Junction site and others will be presented in this paper. The impact of the 3-bit Analog-to-Digital Converter and the automatic stepping of the gain as a function of range in the J-ERS-1 radar receiver on calibration performance has been assessed. Preliminary observations on J-ERS-1 SAR data are that the average Signal-to-Noise ratio is generally fairly low, in the range 5-6dB. Azimuth ambiguity levels are higher than preflight analysis indicated. Over land, the dynamic range in the backscatter at L-band for approximately 36 degree incidence angle is often fairly high.
Freeman, A.↗
Calibration Results for J-ERS-1 SAR Data Produced by the Alaska SAR Facility
The Alaska SAR Facility has been receiving and processing SAR data from the J-ERS-1 satellite since Spring 1992. Corner reflectors have been set up for J-ERS-1 SAR calibration at a site near Delta Junction, in central Alaska. Image quality and calibration analysis results from the Delta Junction site and others will be presented in this paper. The impact of the 3-bit Analog-to-Digital Converter and the automatic stepping of the gain as a function of range in the J-ERS-1 radar receiver on calibration performance has been assessed. Preliminary observations on J-ERS-1 SAR data are that the average Signal-to-Noise ratio is generally fairly low, in the range 5-6 dB. Azimuth ambiguity levels are higher than preflight analysis indicated. Over land, the dynamic range in the backscatter at L-band for approximately 36 degree incidence angle is often fairly high...
Freeman, A.↗
Torsional twist of the SARS ‐ CoV and SARS ‐ CoV ‐2 SUD ‐N and SUD ‐M domains
Abstract Coronavirus non‐structural protein 3 (nsp3) forms hexameric crowns of pores in the double membrane vesicle that houses the replication–transcription complex. Nsp3 in SARS‐like viruses has three unique domains absent in other coronavirus nsp3 proteins. Two of these, SUD‐N (Macrodomain 2) and SUD‐M (Macrodomain 3), form two lobes connected by a peptide linker and an interdomain disulfide bridge. We resolve the first complete x‐ray structure of SARS‐CoV SUD‐N/M as well as a mutant variant of SARS‐CoV‐2 SUD‐N/M modified to restore cysteines for interdomain disulfide bond naturally lost by evolution. Comparative analysis of all structures revealed SUD‐N and SUD‐M are not rigidly associated but rather have significant rotational flexibility. Phylogenetic analysis supports that the potential to form the disulfide bond is common across betacoronavirus isolates from many bat species and civets, but also one or both of the cysteines that form the disulfide bond are absent across isolates from bats and pangolins. The absence of these cysteines does not impact viral replication or protein translation.
Rosas‐Lemus, Monica [Department of Microbiology‐Im↗