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1.
Virus Evol ; 6(2): veaa078, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1383237

ABSTRACT

To better understand the genetic diversity, host associations and evolution of coronaviruses (CoVs) in China we analyzed a total of 696 rodents encompassing 16 different species sampled from Zhejiang and Yunnan provinces. Based on reverse transcriptase PCR-based CoV screening of fecal samples and subsequent sequence analysis of the RNA-dependent RNA polymerase gene, we identified CoVs in diverse rodent species, comprising Apodemus agrarius, Apodemus chevrieri, Apodemus latronum, Bandicota indica, Eothenomys cachinus, Eothenomys miletus, Rattus andamanensis, Rattus norvegicus, and Rattus tanezumi. CoVs were particularly commonplace in A. chevrieri, with a detection rate of 12.44 per cent (24/193). Genetic and phylogenetic analysis revealed the presence of three groups of CoVs carried by a range of rodents that were closely related to the Lucheng Rn rat CoV (LRNV), China Rattus CoV HKU24 (ChRCoV_HKU24), and Longquan Rl rat CoV (LRLV) identified previously. One newly identified A. chevrieri-associated virus closely related to LRNV lacked an NS2 gene. This virus had a similar genetic organization to AcCoV-JC34, recently discovered in the same rodent species in Yunnan, suggesting that it represents a new viral subtype. Notably, additional variants of LRNV were identified that contained putative non-structural (NS)2b genes located downstream of the NS2 gene that were likely derived from the host genome. Recombination events were also identified in the open reading frame (ORF) 1a gene of Lijiang-71. In sum, these data reveal the substantial genetic diversity and genomic complexity of rodent-borne CoVs, and extend our knowledge of these major wildlife virus reservoirs.

2.
Cell Res ; 31(8): 847-860, 2021 08.
Article in English | MEDLINE | ID: covidwho-1387284

ABSTRACT

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Subject(s)
Antiviral Agents/metabolism , COVID-19/pathology , Coronavirus Envelope Proteins/metabolism , Respiratory Distress Syndrome/etiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Apoptosis , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Coronavirus Envelope Proteins/antagonists & inhibitors , Coronavirus Envelope Proteins/genetics , Cytokines/metabolism , Disease Models, Animal , Half-Life , Humans , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutagenesis, Site-Directed , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Spleen/metabolism , Spleen/pathology , Viral Load , Virulence
3.
Cell Res ; 31(8): 847-860, 2021 08.
Article in English | MEDLINE | ID: covidwho-1265947

ABSTRACT

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Subject(s)
Antiviral Agents/metabolism , COVID-19/pathology , Coronavirus Envelope Proteins/metabolism , Respiratory Distress Syndrome/etiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Apoptosis , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Coronavirus Envelope Proteins/antagonists & inhibitors , Coronavirus Envelope Proteins/genetics , Cytokines/metabolism , Disease Models, Animal , Half-Life , Humans , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutagenesis, Site-Directed , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Spleen/metabolism , Spleen/pathology , Viral Load , Virulence
4.
Science ; 371(6536): 1374-1378, 2021 03 26.
Article in English | MEDLINE | ID: covidwho-1255508

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/pathology , COVID-19/virology , Cell Line , Cell Survival/drug effects , Chemokine CXCL10/metabolism , Disease Models, Animal , Drug Design , Humans , Interferon-beta/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Oligopeptides , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , Protease Inhibitors/toxicity , Rats , Rats, Sprague-Dawley , Viral Load/drug effects , Virus Replication
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