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1.
Neuropharmacology ; 207: 108935, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1586929

ABSTRACT

AIMS: Acetaminophen or paracetamol (PAR), the recommended antipyretic in COVID-19 and clinically used to alleviate stroke-associated hyperthermia interestingly activates cannabinoid receptor (CB1) through its AM404 metabolite, however, to date, no study reports the in vivo activation of PAR/AM404/CB1 axis in stroke. The current study deciphers the neuroprotective effect off PAR in cerebral ischemia/reperfusion (IR) rat model and unmasks its link with AM404/CB1/PI3K/Akt axis. MATERIALS AND METHODS: Animals were allocated into 5 groups: (I) sham-operated (SO), (II) IR, (III) IR + PAR (100 mg/kg), (IV) IR + PAR (100 mg/kg) + URB597; anandamide degradation inhibitor (0.3 mg/kg) and (V) IR + PAR (100 mg/kg) + AM4113; CB1 Blocker (5 mg/kg). All drugs were intraperitoneally administered at the inception of the reperfusion period. KEY FINDINGS: PAR administration alleviated the cognitive impairment in the Morris Water Maze as well as hippocampal histopathological and immunohistochemical examination of GFAP. The PAR signaling was associated with elevation of anandamide level, CB1 receptor expression and survival proteins as pS473-Akt. P(tyr202/thr204)-ERK1/2 and pS9-GSK3ß. Simultaneously, PAR increased hippocampal BDNF and ß-arrestin1 levels and decreased glutamate level. PAR restores the deranged redox milieu induced by IR Injury, by reducing lipid peroxides, myeloperoxidase activity and NF-κB and increasing NPSH, total antioxidant capacity, nitric oxide and Nrf2 levels. The pre-administration of AM4113 reversed PAR effects, while URB597 potentiated them. SIGNIFICANCE: PAR poses a significant neuroprotective effect which may be mediated, at least in part, via activation of anandamide/CB1/PI3K/Akt pathway in the IR rat model.


Subject(s)
Acetaminophen/pharmacology , Antipyretics/pharmacology , Benzamides/pharmacology , Carbamates/pharmacology , Enzyme Inhibitors/pharmacology , Hippocampus/drug effects , Phosphatidylinositol 3-Kinases/drug effects , Proto-Oncogene Proteins c-akt/drug effects , Receptor, Cannabinoid, CB1/metabolism , Reperfusion Injury/metabolism , Amidohydrolases/antagonists & inhibitors , Animals , Arachidonic Acids/metabolism , Cannabinoid Receptor Antagonists/pharmacology , Endocannabinoids/metabolism , Hippocampus/blood supply , Hippocampus/metabolism , Hippocampus/physiopathology , Phosphatidylinositol 3-Kinases/metabolism , Polyunsaturated Alkamides/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Reperfusion Injury/physiopathology
2.
Biochem Biophys Res Commun ; 571: 26-31, 2021 09 24.
Article in English | MEDLINE | ID: covidwho-1312941

ABSTRACT

The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new virus particle production. Here, we screened non-nucleoside antivirals and found three out of them to be strongest in binding to RdRp out of which two retained binding even using molecular dynamic simulations. We propose these two drugs as potential RdRp inhibitors which need further in-depth testing.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Amides/pharmacology , Antiviral Agents/chemistry , Benzimidazoles/pharmacology , COVID-19/virology , Carbamates/pharmacology , Catalytic Domain , Computer Simulation , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Cyclopropanes/pharmacology , Drug Evaluation, Preclinical , Drug Repositioning , Fluorenes/pharmacology , Humans , Lactams, Macrocyclic/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Proline/analogs & derivatives , Proline/pharmacology , Protein Conformation , Quinoxalines/pharmacology , Sulfonamides/pharmacology
3.
Sci Rep ; 11(1): 10290, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1228274

ABSTRACT

As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, - 54.8 and - 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.


Subject(s)
Amides/pharmacology , Carbamates/pharmacology , Cyclopropanes/pharmacology , Drug Repositioning , Enzyme Inhibitors/pharmacology , Quinoxalines/pharmacology , RNA Helicases/antagonists & inhibitors , SARS-CoV-2/enzymology , Sulfonamides/pharmacology , Triazoles/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning/methods , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Domains/drug effects , RNA Helicases/chemistry , RNA Helicases/metabolism , SARS-CoV-2/drug effects , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Viral Proteins/metabolism
4.
Sci Rep ; 11(1): 7307, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1164913

ABSTRACT

Outcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.


Subject(s)
Amides/metabolism , Amides/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Carbamates/metabolism , Carbamates/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Cyclopropanes/metabolism , Cyclopropanes/pharmacology , Quinoxalines/metabolism , Quinoxalines/pharmacology , Sulfonamides/metabolism , Sulfonamides/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/metabolism , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Drug Repositioning , Humans , Models, Molecular , Molecular Dynamics Simulation , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , Virus Internalization/drug effects
5.
J Biol Chem ; 296: 100470, 2021.
Article in English | MEDLINE | ID: covidwho-1101336

ABSTRACT

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.


Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Dioxanes/pharmacology , Glucosyltransferases/antagonists & inhibitors , Glycosphingolipids/antagonists & inhibitors , Influenza A Virus, H1N1 Subtype/drug effects , Pyrrolidines/pharmacology , Quinuclidines/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/virology , Carbamates/chemical synthesis , Cell Membrane/drug effects , Cell Membrane/enzymology , Cell Membrane/virology , Chlorocebus aethiops , Clinical Trials, Phase III as Topic , Dioxanes/chemical synthesis , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Gene Expression Regulation , Glucosyltransferases/genetics , Glucosyltransferases/metabolism , Glycosphingolipids/biosynthesis , Host-Pathogen Interactions/genetics , Humans , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/drug therapy , Influenza, Human/enzymology , Influenza, Human/virology , Madin Darby Canine Kidney Cells , Pyrrolidines/chemical synthesis , Quinuclidines/chemical synthesis , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Signal Transduction , Vero Cells , Virus Replication/drug effects
6.
Virus Res ; 292: 198246, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-974719

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Carbazoles/pharmacology , Cytokines/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , COVID-19/drug therapy , Chlorocebus aethiops , Cytokine Release Syndrome/drug therapy , Cytokines/immunology , HeLa Cells , Humans , Inflammation/drug therapy , Inflammation/virology , Vero Cells
7.
Pharmacol Res Perspect ; 8(6): e00674, 2020 12.
Article in English | MEDLINE | ID: covidwho-893251

ABSTRACT

SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected 3'-fluoro-3'-deoxythymidine triphosphate and 3'-azido-3'-deoxythymidine triphosphate, which are the active forms of two other anti-viral agents, Alovudine and AZT (an FDA-approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Betacoronavirus/enzymology , COVID-19 , Carbamates/pharmacology , Coronavirus Infections/virology , Dideoxynucleotides/pharmacology , Drug Combinations , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Sofosbuvir/pharmacology , Thymine Nucleotides/pharmacology , Zidovudine/analogs & derivatives , Zidovudine/pharmacology
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