SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
TL;DR: It is demonstrated that SARS-CoV-2 uses the SARS -CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming, and it is shown that the sera from convalescent SARS patients cross-neutralized Sars-2-S-driven entry.
About: This article is published in Cell.The article was published on 2020-04-16 and is currently open access. It has received 15362 citations till now. The article focuses on the topics: Proteases.
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TL;DR: Of nearly 900,000 candidate culprit variants analyzed as part of the multi-layer screening effort described herein, only five survive and belong to the HDAC6 and IRAK1 genes.
Abstract: Reportable COVID-19 infection rates vary radically from country to country. Remarkably, the reported rates in western Europe are more than an order of magnitude greater than in the tropics and sub-tropics. This suggests a common human genetic variant may be the primary culprit behind reportable COVID-19 infections. Of nearly 900,000 candidate culprit variants analyzed as part of the multi-layer screening effort described herein, only five survive. Those five candidate culprits belong to the HDAC6 and IRAK1 genes.
4 citations
01 Mar 2021
TL;DR: The therapeutic and vaccine options that are available for COVID-19 6 months after its outbreak are explored, with most noteworthy among the therapeutic options are dexamethasone, remdesivir, Avigan (favipiravir) and convalescent plasma.
Abstract: An outbreak of the coronavirus disease 2019 (COVID-19) caused by an infection of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, China, in December 2019. This new virus belongs to the group of enveloped RNA beta-coronaviruses. Symptoms may differ in various infected persons, but major presentations include dry cough, nasal congestion, shortness of breath, fever, and general malaise. The disease appears to be more severe in patients above the age of 60 years and those with underlying conditions such as diabetes, cancer, cardiovascular diseases, chronic respiratory disease, and hypertension. There is still no approved vaccine against COVID-19, but more than a hundred are at different stages of development. It is known that the development of new drugs takes a relatively long time, so several known and already-approved drugs are being repurposed for the treatment of this disease. In this review, we explore the therapeutic and vaccine options that are available for COVID-19 6 months after its outbreak. Most noteworthy among the therapeutic options are dexamethasone, remdesivir, Avigan (favipiravir) and convalescent plasma.
4 citations
TL;DR: This VSV-CoV-2-S platform allows virus neutralization assays to be performed at BSL-2 and also has applications as a candidate vectored vaccine to elicit protective immunity against SARS-Cov-2.
4 citations
19 Aug 2020
TL;DR: The nature of the emerging COVID-19 global pandemic is summarized while analyzing several factors concerning the etiology of the virus to educate and provide relevant information about the virus.
Abstract: Coronaviruses (COVS) are viruses transmitted through droplets of sputum from an infected person. Analyses identify COVS as zoonotic pathogens, possibly resulting from human-animal contact at animal markets. They share overlapping genetic characteristics with the avian influenza viruses from China. COVS released from humans through droplets of sputum and may land on various surfaces, which poses exposure risks; as studies have shown the virus can exist intact for a relatively long period of time (several days). The recent highly pathogenic COVS outbreak (COVID-19) emerged in Wuhan, China in 2019, include Severe Acute Respiratory Syndrome (SARS-COVS). This highly transmittable disease causes pneumonia and severe respiratory illnesses similar to SARS and MERS; it has a global mortality rate of about 6.13%. The virus has rapidly become a global pandemic, causing major global issues, including health, economic, and age-preference, among other issues. This text summarizes the nature of the emerging COVID-19 global pandemic while analyzing several factors concerning the etiology of the virus. This is done in an urgent effort to educate and provide relevant information about the virus.
4 citations
Cites background from "SARS-CoV-2 Cell Entry Depends on AC..."
...This is facilitated through the transmembrane protease serine 2 (TMPRSS2) for priming, where the virus is activated.(51) In this context, inhibition of TMPRSS2 could block cell entry by COVID-19, reduce the virus replication, and present a possible therapeutic pathways....
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TL;DR: In this paper , an integrative chemogenomics approach based on computational modeling and in vitro enzymatic assays, for repurposing serine-targeted covalent inhibitors.
Abstract: Host cell entry of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is facilitated via priming of its spike glycoprotein by the human transmembrane protease serine 2 (TMPRSS2). Although camostat and nafamostat are two highly potent covalent TMPRSS2 inhibitors, they nevertheless did not hold promise in COVID‐19 clinical trials, presumably due to their short plasma half‐lives. Herein, we report an integrative chemogenomics approach based on computational modeling and in vitro enzymatic assays, for repurposing serine‐targeted covalent inhibitors. This led to the identification of BC‐11 as a covalent TMPRSS2 inhibitor displaying a unique selectivity profile for serine proteases, ascribable to its boronic acid warhead. BC‐11 showed modest inhibition of SARS‐CoV‐2 (omicron variant) spike pseudotyped particles in a cell‐based entry assay, and a combination of BC‐11 and AHN 1‐055 (a spike glycoprotein inhibitor) demonstrated better viral entry inhibition than either compound alone. Given its low molecular weight and good activity against TMPRSS2, BC‐11 qualifies as a good starting point for further structural optimizations.
4 citations
References
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TL;DR: The epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of patients with laboratory-confirmed 2019-nCoV infection in Wuhan, China, were reported.
36,578 citations
"SARS-CoV-2 Cell Entry Depends on AC..." refers background in this paper
...Infections were also detected in 24 countries outside China and were associated with international travel....
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...Subsequently, human-to-human transmission occurred (Chan et al., 2020) and the disease, now termed coronavirus disease 19 (COVID-19) rapidly spread within China....
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...On February 12, 2020, a total of 44,730 laboratoryconfirmed infections were reported in China, including 8,204 Cell 181, 271–280, April 16, 2020 ª 2020 Elsevier Inc. 271 (A) Schematic illustration of SARS-S including functional domains (RBD, receptor binding domain; RBM, receptor bindingmotif; TD, transmembrane domain) and proteolytic cleavage sites (S1/S2, S20 )....
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...The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency....
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...In December 2019, a new infectious respiratory disease emerged in Wuhan, Hubei province, China (Huang et al., 2020; Wang et al., 2020; Zhu et al., 2020)....
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TL;DR: The Molecular Evolutionary Genetics Analysis (Mega) software implements many analytical methods and tools for phylogenomics and phylomedicine and has additionally been upgraded to use multiple computing cores for many molecular evolutionary analyses.
Abstract: The Molecular Evolutionary Genetics Analysis (Mega) software implements many analytical methods and tools for phylogenomics and phylomedicine. Here, we report a transformation of Mega to enable cross-platform use on Microsoft Windows and Linux operating systems. Mega X does not require virtualization or emulation software and provides a uniform user experience across platforms. Mega X has additionally been upgraded to use multiple computing cores for many molecular evolutionary analyses. Mega X is available in two interfaces (graphical and command line) and can be downloaded from www.megasoftware.net free of charge.
21,952 citations
TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Abstract: In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).
21,455 citations
TL;DR: Identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China, and it is shown that this virus belongs to the species of SARSr-CoV, indicates that the virus is related to a bat coronav virus.
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.
16,857 citations
TL;DR: The findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.
7,392 citations
"SARS-CoV-2 Cell Entry Depends on AC..." refers background in this paper
...Subsequently, human-to-human transmission occurred (Chan et al., 2020) and the disease, now termed coronavirus disease 19 (COVID-19) rapidly spread within China....
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