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1.
J Nat Prod ; 85(2): 327-336, 2022 02 25.
Article in English | MEDLINE | ID: covidwho-1655431

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 5 million deaths worldwide to date. Due to the limited therapeutic options so far available, target-based virtual screening with LC/MS support was applied to identify the novel and high-content compounds 1-4 with inhibitory effects on SARS-CoV-2 in Vero E6 cells from the plant Dryopteris wallichiana. These compounds were also evaluated against SARS-CoV-2 in Calu-3 cells and showed unambiguous inhibitory activity. The inhibition assay of targets showed that compounds 3 and 4 mainly inhibited SARS-CoV-2 3CLpro, with effective Kd values. Through docking and molecular dynamics modeling, the binding site is described, providing a comprehensive understanding of 3CLpro and interactions for 3, including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring. Compounds 3 and 4 represent new, potential lead compounds for the development of anti-SARS-CoV-2 drugs. This study has led to the development of a target-based virtual screening method for exploring the potency of natural products and for identifying natural bioactive compounds for possible COVID-19 treatment.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Microbial Sensitivity Tests/methods , Phloroglucinol/pharmacology , SARS-CoV-2/drug effects , Terpenes/pharmacology , Chromatography, High Pressure Liquid , Chromatography, Liquid , Crystallography, X-Ray , Drug Delivery Systems , Dryopteris/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Docking Simulation , Molecular Structure , Virtual Reality
3.
Acta Pharmacol Sin ; 41(9): 1167-1177, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-691161

ABSTRACT

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections , Drugs, Chinese Herbal , Flavanones , Flavonoids , Pandemics , Pneumonia, Viral , Virus Replication/drug effects , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/physiology , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Enzyme Assays , Flavanones/chemistry , Flavanones/pharmacokinetics , Flavonoids/chemistry , Flavonoids/pharmacokinetics , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Vero Cells , Virus Replication/physiology
4.
Emerg Microbes Infect ; 9(1): 386-389, 2020.
Article in English | MEDLINE | ID: covidwho-1080

ABSTRACT

In December 2019, a novel coronavirus (2019-nCoV) caused an outbreak in Wuhan, China, and soon spread to other parts of the world. It was believed that 2019-nCoV was transmitted through respiratory tract and then induced pneumonia, thus molecular diagnosis based on oral swabs was used for confirmation of this disease. Likewise, patient will be released upon two times of negative detection from oral swabs. However, many coronaviruses can also be transmitted through oral-fecal route by infecting intestines. Whether 2019-nCoV infected patients also carry virus in other organs like intestine need to be tested. We conducted investigation on patients in a local hospital who were infected with this virus. We found the presence of 2019-nCoV in anal swabs and blood as well, and more anal swab positives than oral swab positives in a later stage of infection, suggesting shedding and thereby transmitted through oral-fecal route. We also showed serology test can improve detection positive rate thus should be used in future epidemiology. Our report provides a cautionary warning that 2019-nCoV may be shed through multiple routes.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/transmission , Feces/virology , Pneumonia, Viral/transmission , Virus Shedding , COVID-19 , China , Coronavirus Infections/blood , Humans , Pneumonia, Viral/blood , SARS-CoV-2
5.
Nature ; 579(7798): 270-273, 2020 03.
Article in English | MEDLINE | ID: covidwho-246

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.


Subject(s)
Betacoronavirus/classification , Betacoronavirus/genetics , Chiroptera/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Disease Outbreaks , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Viral/blood , Betacoronavirus/metabolism , Betacoronavirus/ultrastructure , COVID-19 , Cell Line , China/epidemiology , Chlorocebus aethiops , Female , Genome, Viral/genetics , Humans , Male , Peptidyl-Dipeptidase A/metabolism , Phylogeny , SARS Virus/classification , SARS Virus/genetics , SARS-CoV-2 , Sequence Homology, Nucleic Acid , Severe Acute Respiratory Syndrome , Vero Cells
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