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HGNC Genes

SARS-CoV-2 proteins

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    On the molecular mechanism of SARS-CoV-2 retention in the upper respiratory tract

    Authors: Kristina A Paris; Ulises Santiago; Carlos J. Camacho

    doi:10.1101/2020.07.29.227389 Date: 2020-07-29 Source: bioRxiv

    Cell surface receptor HGNC engagement is a critical aspect of viral infection MESHD. At low pH, binding of SARS-CoV MESHD and its ACE2 HGNC receptor has a tight interaction that catalyzes the fusion of the spike and endosomal membranes followed by genome release. Largely overlooked has been the role of neutral pH in the respiratory tract, where we find that SARS-CoV MESHD stabilizes a transition state that enhances the off-rate from its receptor. An alternative pH-switch is found in CoV-2-like coronaviruses of tropical pangolins, but with a reversed phenotype where the tight interaction with ACE2 HGNC is at neutral pH. We show that a single point mutation in pangolin-CoV, unique to CoV-2, that deletes the last His residue in their receptor binding domain perpetuates this tight interaction independent of pH. This tight bond, not present in previous respiratory syndromes, implies that CoV-2 stays bound to the highly expressed ACE2 HGNC receptors in the nasal cavity about 100 times longer than CoV. This finding supports the unfamiliar pathology of CoV-2, observed virus retention in upper respiratory tract1, longer incubation times and extended periods of shedding. Implications to combat pandemics that, like SARS-CoV-2, export evolutionarily successful strains via higher transmission rates due to retention in nasal epithelium and their evolutionary origin are discussed.

    Loss of pH switch unique to SARS-CoV2 supports unfamiliar virus pathology

    Authors: Carlos J. Camacho; Kristina A. Paris; Ulises Santiago

    doi:10.1101/2020.06.16.155457 Date: 2020-06-23 Source: bioRxiv

    Cell surface receptor HGNC engagement is a critical aspect of viral infection MESHD. This paper compares the dynamics of virus-receptor interactions for SARS-CoV MESHD (CoV1) and CoV2. At low (endosomal) pH, the binding free energy landscape of CoV1 and CoV2 interactions with the angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) receptor is almost the same. However, at neutral pH the landscape is different due to the loss of a pH-switch (His445Lys) in the receptor binding domain (RBD) of CoV2 relative to CoV1. Namely, CoV1 stabilizes a transition state above the bound state. In situations where small external strains are applied by, say, shear flow in the respiratory system, the off rate of the viral particle is enhanced. As a result, CoV1 virions are expected to detach from cell surfaces in time scales that are much faster than the time needed for other receptors to reach out and stabilize virus attachment. On the other hand, the loss of this pH-switch, which sequence alignments show is unique to CoV2, eliminates the transition state and allows the virus to stay bound to the ACE2 receptor for time scales compatible with the recruitment of additional ACE2 HGNC receptors diffusing in the cell membrane. This has important implications for viral infection MESHD and its pathology. CoV1 does not trigger high infectivity in the nasal area because it either rapidly drifts down the respiratory tract or is exhaled. By contrast, this novel mutation in CoV2 should not only retain the infection in the nasal cavity until ACE2 HGNC-rich cells are sufficiently depleted, but also require fewer particles for infection. This mechanism explains observed longer incubation times, extended period of viral shedding, and higher rate of transmission. These considerations governing viral entry suggest that number of ACE2 HGNC-rich cells in human nasal mucosa, which should be significantly smaller for children (and females relative to males), should also correlate with onset of viral load that could be a determinant of higher virus susceptibility. Critical implications for the development of new vaccines to combat current and future pandemics that, like SARS-CoV2, export evolutionarily successful strains via higher transmission rates by viral retention in nasal epithelium are also discussed.

    Bcr-Abl tyrosine kinase inhibitor imatinib as a potential drug for COVID-19 MESHD

    Authors: Nirmitee Sanjay Mulgaonkar; Haoqi Wang; Samavath Mallawarachchi; Daniel Ruzek; Byron Martina; Sandun Fernando

    doi:10.1101/2020.06.18.158196 Date: 2020-06-18 Source: bioRxiv

    The rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) pandemic, poses an immediate need for potent drugs that can help contain the outbreak. Enveloped viruses infect MESHD the host cell by cellular membrane fusion, a crucial mechanism required for virus replication. The SARS-CoV-2 spike PROTEIN glycoprotein, due to its primary interaction with the human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) cell-surface receptor HGNC, is considered as a potential target for drug development. Based on in silico screening followed by in vitro studies, here we report that the existing FDA-approved Bcr-Abl tyrosine kinase inhibitor, imatinib, inhibits SARS-CoV-2 with an IC50 of 130 nM. We provide initial evidence that inhibition of virus fusion may explain the antiviral action of imatinib. This finding is significant since pinpointing the mode of action allows evaluating the drugs affinity to the SARS-CoV-2-specific target protein, and in turn, helps make inferences on the potency of the drug and evidence-based recommendations on its dosage. To this end, we provide evidence that imatinib binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD protein with an affinity at micromolar, i.e., 2.32 {+/-} 0.9 {micro}M, levels. We also show that imatinib inhibits other coronaviruses, SARS-CoV MESHD and MERS-CoV, possibly via fusion inhibition. Based on promising in vitro results, we propose the Abl kinase inhibitor (ATKI), imatinib, to be a viable repurposable drug candidate for further clinical validation against COVID-19 MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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