Résumé
The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Sujets)
Humains , Antiviraux/composition chimique , COVID-19 , Traitements médicamenteux de la COVID-19 , Tests de criblage à haut débit , Simulation de docking moléculaire , Inhibiteurs de protéases/composition chimique , SARS-CoV-2/enzymologie , Protéines virales non structuralesRésumé
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 (M
Sujets)
Humains , Antiviraux/usage thérapeutique , Sites de fixation , COVID-19/virologie , Protéases de type papaïne des coronavirus/métabolisme , Cristallographie aux rayons X , Évaluation préclinique de médicament , Repositionnement des médicaments , Tests de criblage à haut débit/méthodes , Imidazoles/usage thérapeutique , Concentration inhibitrice 50 , Simulation de dynamique moléculaire , Mutagenèse dirigée , Naphtoquinones/usage thérapeutique , Inhibiteurs de protéases/usage thérapeutique , Structure tertiaire des protéines , Protéines recombinantes/isolement et purification , SARS-CoV-2/isolement et purificationRésumé
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Sujets)
Animaux , Humains , Souris , Antiviraux , Pharmacologie , Utilisations thérapeutiques , Betacoronavirus , Physiologie , Sites de fixation , Lignée cellulaire , Infections à coronavirus , Traitement médicamenteux , Virologie , Crotonates , Pharmacologie , Syndrome de libération de cytokines , Traitement médicamenteux , Évaluation préclinique de médicament , Techniques de knock-out de gènes , Virus de la grippe A , Léflunomide , Pharmacologie , Souris de lignée BALB C , Infections à Orthomyxoviridae , Traitement médicamenteux , Oséltamivir , Utilisations thérapeutiques , Oxidoreductases , Métabolisme , Pandémies , Pneumopathie virale , Traitement médicamenteux , Virologie , Liaison aux protéines , Pyrimidines , Virus à ARN , Physiologie , Relation structure-activité , Toluidines , Pharmacologie , Ubiquinones , Métabolisme , Réplication viraleRésumé
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Sujets)
Animaux , Humains , Souris , Antiviraux , Pharmacologie , Utilisations thérapeutiques , Betacoronavirus , Physiologie , Sites de fixation , Lignée cellulaire , Infections à coronavirus , Traitement médicamenteux , Virologie , Crotonates , Pharmacologie , Syndrome de libération de cytokines , Traitement médicamenteux , Évaluation préclinique de médicament , Techniques de knock-out de gènes , Virus de la grippe A , Léflunomide , Pharmacologie , Souris de lignée BALB C , Infections à Orthomyxoviridae , Traitement médicamenteux , Oséltamivir , Utilisations thérapeutiques , Oxidoreductases , Métabolisme , Pandémies , Pneumopathie virale , Traitement médicamenteux , Virologie , Liaison aux protéines , Pyrimidines , Virus à ARN , Physiologie , Relation structure-activité , Toluidines , Pharmacologie , Ubiquinones , Métabolisme , Réplication viraleRésumé
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.