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1.
Acta Pharmacol Sin ; 43(4): 788-796, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1343437

ABSTRACT

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , COVID-19/drug therapy , Humans , Protein Binding , SARS-CoV-2
2.
MedComm (2020) ; 2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1287380

ABSTRACT

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants has posed a serious global public health emergency. Therapeutic interventions or vaccines are urgently needed to treat and prevent the further dissemination of this contagious virus. This study described the identification of neutralizing receptor-binding domain (RBD)-specific antibodies from mice through vaccination with a recombinant SARS-CoV-2 RBD. RBD-targeted monoclonal antibodies (mAbs) with distinct function and epitope recognition were selected to understand SARS-CoV-2 neutralization. High-affinity RBD-specific antibodies exhibited high potency in neutralizing both live and pseudotype SARS-CoV-2 viruses and the SARS-CoV-2 pseudovirus particle containing the spike protein S-RBDV367F mutant (SARS-CoV-2(V367F)). These results demonstrated that these antibodies recognize four distinct groups (I-IV) of epitopes on the RBD and that mAbs targeting group I epitope can be used in combination with mAbs recognizing groups II and/or IV epitope to make mAb cocktails against SARS-CoV-2 and its mutants. Moreover, structural characterization reveals that groups I, III, and IV epitopes are closely located to an RBD hotspot. The identification of RBD-specific antibodies and cocktails may provide an effective therapeutic and prophylactic intervention against SARS-CoV-2 and its isolates.

3.
J Food Prot ; 84(6): 1000-1008, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1239077

ABSTRACT

ABSTRACT: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not a proven foodborne pathogen, the COVID-19 pandemic has put the food system on alert, and food safety has been identified as an important pillar in mitigating the crisis. Therefore, an understanding of how popular media are used as a vital disseminator of food safety and health information for the public is more important than ever. YouTube deserves particular attention as one of the most highly trafficked Web sites on the Internet, especially because YouTube has been blamed during the pandemic for spreading misleading or untrustworthy information that contradicts validated information. This study was conducted to evaluate the food safety information and practices circulating on YouTube during the COVID-19 pandemic and the alignment of these practices with recommendations from government agencies. A search for videos on YouTube was conducted using the key words "food and COVID-19," "food safety and COVID-19," and "groceries and COVID-19." After applying a series of inclusive and exclusive criteria, 85 videos from the United States and Canada were evaluated. More than half (69%) of the videos presented hand washing procedures, 26% showed kitchen disinfection, and most (86%) showed take-out food or grocery store practices. Multiple produce washing procedures were also shown throughout videos. Food was not considered hazardous in 39% of the videos, but 24% mentioned that food packaging is potentially hazardous. Most videos cited government agencies and had a host or guest who was a health care professional, professor, or expert. Three videos were not aligned with a government agency's guideline or information cited; two were presented by a health care professional. These findings reveal the need to develop educational interventions that increase YouTube video host and guest awareness of social media use as a tool for food safety dissemination and the need to provide trustworthy information.


Subject(s)
COVID-19 , Social Media , Canada , Food Safety , Humans , Information Dissemination , Pandemics , SARS-CoV-2 , United States
4.
Protein Cell ; 12(11): 877-888, 2021 11.
Article in English | MEDLINE | ID: covidwho-1188202

ABSTRACT

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 µmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.


Subject(s)
Coronavirus Papain-Like Proteases/chemistry , High-Throughput Screening Assays/methods , Protease Inhibitors/chemistry , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Repositioning , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Naphthoquinones/chemistry , Naphthoquinones/metabolism , Naphthoquinones/therapeutic use , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , SARS-CoV-2/isolation & purification
5.
Stem Cell Res ; 52: 102219, 2021 04.
Article in English | MEDLINE | ID: covidwho-1062599

ABSTRACT

The current COVID-19 pandemic is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). By late October 2020, more than 43 million cases of infections, including over 1.15 million deaths, have been confirmed worldwide. This review focuses on our current understanding of SARS-CoV-2 from the perspective of the three-dimensional (3D) structures of SARS-CoV-2 viral proteins and their implications on therapeutics development against COVID-19.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Antibodies, Viral/chemistry , Genome, Viral , Humans , Ion Channels/chemistry , Protein Conformation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
6.
Nature ; 582(7811): 289-293, 2020 06.
Article in English | MEDLINE | ID: covidwho-608904

ABSTRACT

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 µM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.


Subject(s)
Betacoronavirus/chemistry , Cysteine Endopeptidases/chemistry , Drug Discovery/methods , Models, Molecular , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , COVID-19 , Cells, Cultured/virology , Coronavirus 3C Proteases , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Drug Design , Drug Evaluation, Preclinical , Humans , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , SARS-CoV-2
7.
Cell ; 182(2): 417-428.e13, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-342735

ABSTRACT

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.


Subject(s)
Betacoronavirus/chemistry , Betacoronavirus/enzymology , RNA-Dependent RNA Polymerase/chemistry , Viral Nonstructural Proteins/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus RNA-Dependent RNA Polymerase , Cryoelectron Microscopy , Models, Chemical , Models, Molecular , RNA, Viral/metabolism , SARS-CoV-2 , Transcription, Genetic , Virus Replication
8.
Science ; 368(6492): 779-782, 2020 05 15.
Article in English | MEDLINE | ID: covidwho-47347

ABSTRACT

A novel coronavirus [severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo-electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified ß-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.


Subject(s)
Betacoronavirus/enzymology , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/ultrastructure , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/ultrastructure , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus RNA-Dependent RNA Polymerase , Cryoelectron Microscopy , Drug Design , Models, Molecular , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Multiprotein Complexes/ultrastructure , Protein Conformation, beta-Strand , Protein Domains , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2 , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
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