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Chem Biol Interact ; 335: 109348, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-956088


The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (Mpro) is an important enzyme for viral replication. Small molecules that inhibit this protease could lead to an effective COVID-19 treatment. The 2-pyridone scaffold was previously identified as a possible key pharmacophore to inhibit SARS-CoV-2 Mpro. A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 Mpro was investigated. Thirty-three natural products containing the 2-pyridone scaffold were identified from the literature. An in silico methodology using AutoDock was employed to predict the binding energies and inhibition constants (Ki values) for each 2-pyridone-containing compound with SARS-CoV-2 Mpro. This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 Mpro, and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 Mpro, close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted Ki values <1 µM. Glu-166 formed a key hydrogen bond in the majority of the predicted complexes, while Met-165 had some involvement in the complex binding as a close contact to the ligand. Prominent 2-pyridone compounds were further evaluated for their ADMET properties. This work has identified 2-pyridone natural products with calculated potent inhibitory activity against SARS-CoV-2 Mpro and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.

Antiviral Agents/metabolism , Biological Products/metabolism , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Pyridones/metabolism , SARS-CoV-2/enzymology , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Products/chemistry , Biological Products/pharmacokinetics , Caco-2 Cells , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Humans , Hydrogen Bonding , Molecular Docking Simulation , Molecular Structure , Protein Binding , Pyridones/chemistry , Pyridones/pharmacokinetics
Eur J Pharm Sci ; 157: 105631, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-893750


BACKGROUND: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients. METHODS: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544). RESULTS: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 µM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 µM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group. CONCLUSIONS: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.

Amides , COVID-19 , Dibenzothiepins , Morpholines , Pyrazines , Pyridones , Triazines , Amides/administration & dosage , Amides/blood , Amides/pharmacokinetics , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , COVID-19/blood , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/physiopathology , Dibenzothiepins/administration & dosage , Dibenzothiepins/blood , Dibenzothiepins/pharmacokinetics , Drug Monitoring/methods , Female , Humans , Inhibitory Concentration 50 , Male , Middle Aged , Morpholines/administration & dosage , Morpholines/blood , Morpholines/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/blood , Pyrazines/pharmacokinetics , Pyridones/administration & dosage , Pyridones/blood , Pyridones/pharmacokinetics , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Symptom Assessment , Treatment Outcome , Triazines/administration & dosage , Triazines/blood , Triazines/pharmacokinetics , Viral Load/drug effects