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Chem Commun (Camb) ; 57(67): 8352-8355, 2021 Aug 28.
Article in English | MEDLINE | ID: covidwho-1337131


By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for coordinatively unsaturated DNIC binding using the only known crystal structure of a protein-bound DNIC, PDB- (calculation RMSD = 1.77). From the in silico data the dimeric DNICs TGTA-RRE, [(µ-S-TGTA)Fe(NO)2]2 (TGTA = 1-thio-ß-d-glucose tetraacetate) and TG-RRE, [(µ-S-TG)Fe(NO)2]2 (TG = 1-thio-ß-d-glucose) were identified as promising leads for inhibition via coordinative inhibition at Cys-145 of the SARS-CoV-2 Main Protease (SC2Mpro). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC50 of 38 ± 2 µM for TGTA-RRE and 33 ± 2 µM for TG-RRE. This study presents a simple computational method for predicting DNIC-protein interactions; the in vitro study is consistent with in silico leads.

Enzyme Inhibitors/pharmacology , Iron/pharmacology , Nitrogen Oxides/pharmacology , Peptide Hydrolases/metabolism , SARS-CoV-2/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Iron/chemistry , Models, Molecular , Molecular Structure , Nitrogen Oxides/chemistry , SARS-CoV-2/enzymology
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Article in English | MEDLINE | ID: covidwho-1112035


Surface ozone is a severe air pollution problem in the North China Plain, which is home to 300 million people. Ozone concentrations are highest in summer, driven by fast photochemical production of hydrogen oxide radicals (HOx) that can overcome the radical titration caused by high emissions of nitrogen oxides (NOx) from fuel combustion. Ozone has been very low during winter haze (particulate) pollution episodes. However, the abrupt decrease of NOx emissions following the COVID-19 lockdown in January 2020 reveals a switch to fast ozone production during winter haze episodes with maximum daily 8-h average (MDA8) ozone concentrations of 60 to 70 parts per billion. We reproduce this switch with the GEOS-Chem model, where the fast production of ozone is driven by HOx radicals from photolysis of formaldehyde, overcoming radical titration from the decreased NOx emissions. Formaldehyde is produced by oxidation of reactive volatile organic compounds (VOCs), which have very high emissions in the North China Plain. This remarkable switch to an ozone-producing regime in January-February following the lockdown illustrates a more general tendency from 2013 to 2019 of increasing winter-spring ozone in the North China Plain and increasing association of high ozone with winter haze events, as pollution control efforts have targeted NOx emissions (30% decrease) while VOC emissions have remained constant. Decreasing VOC emissions would avoid further spreading of severe ozone pollution events into the winter-spring season.

Air Pollution/analysis , Ozone/analysis , Particulate Matter/analysis , Seasons , Volatile Organic Compounds , COVID-19 , China , Crops, Agricultural , Environmental Monitoring , Environmental Pollution , Humans , Nitrogen Oxides/chemistry , Pandemics , Public Health
J Mol Graph Model ; 104: 107834, 2021 05.
Article in English | MEDLINE | ID: covidwho-1009678


Since 2020, the world is facing the first global pandemic of 21st century. Among all the solutions proposed to treat this new strain of coronavirus, named SARS-CoV-2, the vaccine seems a promising way but the delays are too long to be implemented quickly. In the emergency, a dual therapy has shown its effectiveness but has also provoked a set of debates around the dangerousness of a particular molecule, hydroxychloroquine. In particular, the doses to be delivered, according to the studies, were well beyond the acceptable doses to support the treatment without side effects. We propose here to use all the advantages of nanovectorization to address this question of concentration. Using quantum and classical simulations we will show in particular that drug transport on boron nitrogen oxide nanosheets increases the effectiveness of the action of these drugs. This will definitely allow to decrease the drug quantity needing to face the disease.

Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , Azithromycin/chemistry , Hydroxychloroquine/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Azithromycin/pharmacology , Binding Sites , Boron Compounds/chemistry , COVID-19/drug therapy , COVID-19/virology , Drug Delivery Systems/methods , Drug Dosage Calculations , Humans , Hydroxychloroquine/pharmacology , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Nanomedicine/methods , Nanostructures/chemistry , Nitrogen Oxides/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Quantum Theory , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics