Résumé
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.