ABSTRACT
The pandemic infectious disease (Covid-19) caused by the coronavirus (SARS-CoV2) is spreading rapidly around the world. Covid-19 does an irreparable harm to the health and life of people. It also has a negative financial impact on the economies of most countries of the world. In this regard, the issue of creating drugs aimed at combating this disease is especially acute. In this work, molecular docking was used to study the docking of 23 compounds with QRF3a SARS-CoV2. The performed in silico modeling made it possible to identify leading compounds capable of exerting a potential inhibitory and virucidal effect. The leading compounds include chlorin (a drug used in PDT), iron(III)protoporphyrin (endogenous porphyrin), and tetraanthraquinone porphyrazine (an exogenous substance). Having taken into consideration the localization of ligands in the QRF3a SARS-CoV2, we have made an assumption about their influence on the pathogenesis of Covid-19. The interaction of chlorin, iron(III)protoporphyrin and protoporphyrin with the viral protein ORF3a were studied by fluorescence and UV-Vis spectroscopy. The obtained experimental results confirm the data of molecular docking. The results showed that a viral protein binds to endogenous porphyrins and chlorins, moreover, chlorin is a competitive ligand for endogenous porphyrins. Chlorin should be considered as a promising drug for repurposing.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/metabolism , Heterocyclic Compounds/chemistry , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/metabolism , Viroporin Proteins/chemistry , Viroporin Proteins/metabolism , Binding Sites , Drug Repositioning , Heterocyclic Compounds/metabolism , Ligands , Molecular Docking Simulation , Porphyrins/chemistry , Porphyrins/metabolism , Protoporphyrins/chemistry , Protoporphyrins/metabolism , SARS-CoV-2/drug effects , Viroporin Proteins/antagonists & inhibitors , COVID-19 Drug TreatmentABSTRACT
SARS-CoV-2 ORF3a is a putative viral ion channel implicated in autophagy inhibition, inflammasome activation and apoptosis. 3a protein and anti-3a antibodies are found in infected patient tissues and plasma. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, suggesting it could be an effective target for vaccines or therapeutics. Here, we present structures of SARS-CoV-2 3a determined by cryo-EM to 2.1-Å resolution. 3a adopts a new fold with a polar cavity that opens to the cytosol and membrane through separate water- and lipid-filled openings. Hydrophilic grooves along outer helices could form ion-conduction paths. Using electrophysiology and fluorescent ion imaging of 3a-reconstituted liposomes, we observe Ca2+-permeable, nonselective cation channel activity, identify mutations that alter ion permeability and discover polycationic inhibitors of 3a activity. 3a-like proteins are found across coronavirus lineages that infect bats and humans, suggesting that 3a-targeted approaches could treat COVID-19 and other coronavirus diseases.
Subject(s)
Cryoelectron Microscopy , Nanostructures , SARS-CoV-2 , Viroporin Proteins/chemistry , Viroporin Proteins/ultrastructure , Animals , Calcium/metabolism , Chiroptera/virology , Coronaviridae , Electrophysiology , Fluorescence , Humans , Ion Transport , Liposomes , Models, Molecular , Nanostructures/chemistry , Nanostructures/ultrastructure , Open Reading Frames , Optical Imaging , Reproducibility of Results , SARS-CoV-2/chemistry , SARS-CoV-2/ultrastructure , Sequence Homology , Viral Proteins/chemistry , Viral Proteins/ultrastructure , Viroporin Proteins/antagonists & inhibitorsABSTRACT
The COVID-19 epidemic is one of the most influential epidemics in history. Understanding the impact of coronaviruses (CoVs) on host cells is very important for disease treatment. The SARS-CoV-2 envelope (E) protein is a small structural protein involved in many aspects of the viral life cycle. The E protein promotes the packaging and reproduction of the virus, and deletion of this protein weakens or even abolishes the virulence. This review aims to establish new knowledge by combining recent advances in the study of the SARS-CoV-2 E protein and by comparing it with the SARS-CoV E protein. The E protein amino acid sequence, structure, self-assembly characteristics, viroporin mechanisms and inhibitors are summarized and analyzed herein. Although the mechanisms of the SARS-CoV-2 and SARS-CoV E proteins are similar in many respects, specific studies on the SARS-CoV-2 E protein, for both monomers and oligomers, are still lacking. A comprehensive understanding of this protein should prompt further studies on the design and characterization of effective targeted therapeutic measures.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Coronavirus Envelope Proteins/antagonists & inhibitors , Coronavirus Envelope Proteins/metabolism , SARS-CoV-2/physiology , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , COVID-19/metabolism , COVID-19/virology , Coronavirus Envelope Proteins/chemistry , Humans , Models, Molecular , Protein Conformation , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Sequence Alignment , Viroporin Proteins/antagonists & inhibitors , Viroporin Proteins/chemistry , Viroporin Proteins/metabolismABSTRACT
The etiological agent of the COVID-19 pandemic is SARS-CoV-2. As a member of the Coronaviridae, the enveloped pathogen has several membrane proteins, of which two, E and 3a, were suggested to function as ion channels. In an effort to increase our treatment options, alongside providing new research tools, we have sought to inhibit the 3a channel by targeted drug repurposing. To that end, using three bacteria-based assays, we screened a library of 2839 approved-for-human-use drugs and identified the following potential channel-blockers: Capreomycin, Pentamidine, Spectinomycin, Kasugamycin, Plerixafor, Flumatinib, Litronesib, Darapladib, Floxuridine and Fludarabine. The stage is now set for examining the activity of these compounds in detailed electrophysiological studies and their impact on the whole virus with appropriate biosafety measures.