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1.
J Mol Model ; 28(11): 354, 2022 Oct 12.
Article in English | MEDLINE | ID: covidwho-2059878

ABSTRACT

The papain-like protease (PLpro) from SARS-CoV-2 is an important target for the development of antivirals against COVID-19. The safe drug disulfiram (DSF) presents antiviral activity inhibiting PLpro in vitro, and it is under clinical trial studies, indicating to be a promising anti-COVID-19 drug. In this work, we aimed to understand the mechanism of PLpro inhibition by DSF and verify if DSF metabolites and derivatives could be potential inhibitors too. Molecular docking, DFT, and ADMET techniques were applied. The carbamoylation of the active site cysteine residue by DSF metabolite (DETC-MeSO) is kinetically and thermodynamically favorable (ΔG‡ = 3.15 and ΔG = - 12.10 kcal mol-1, respectively). Our results strongly suggest that the sulfoxide metabolites from DSF are promising covalent inhibitors of PLpro and should be tested in in vitro and in vivo assays to confirm their antiviral action.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Clinical Trials as Topic , Computational Chemistry , Cysteine , Disulfiram/metabolism , Disulfiram/pharmacology , Humans , Molecular Docking Simulation , Papain , Peptide Hydrolases , Protease Inhibitors/chemistry , Sulfoxides
2.
Molecules ; 27(17)2022 Aug 31.
Article in English | MEDLINE | ID: covidwho-2006140

ABSTRACT

Disulfiram (DS), known as an anti-alcoholism drug, has shown a potent antiviral activity. Still, the potential clinical application of DS is limited by its low water solubility and rapid metabolism. Cyclodextrins (CDs) have been widely used to improve the solubility of drugs in water. In this study, five concentrations of hydroxypropyl ß-cyclodextrin (HP) and sulfobutyl ether ß-cyclodextrin (SBE) were used to form inclusion complexes of DS for enhanced solubility. Solutions were freeze-dried, and the interaction between DS and CD was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). In addition, the nebulization properties of the DS-CD solutions were studied. The aqueous solubility of DS increased significantly when loaded to either of both CDs. The phase solubility of both complexes was a linear function of the CD concentration (AL type). Furthermore, physicochemical characterization studies showed a potent inclusion of the drug in the CD-DS complexes. Aerosolization studies demonstrated that these formulations are suitable for inhalation. Overall, the CD inclusion complexes have great potential for the enhancement of DS solubility. However, further studies are needed to assess the efficacy of DS-CD inclusion complexes against SARS-CoV-2 via nebulization.


Subject(s)
COVID-19 Drug Treatment , Cyclodextrins , beta-Cyclodextrins , 2-Hydroxypropyl-beta-cyclodextrin/chemistry , Calorimetry, Differential Scanning , Cyclodextrins/chemistry , Cyclodextrins/pharmacology , Disulfiram/pharmacology , Humans , SARS-CoV-2 , Solubility , Spectroscopy, Fourier Transform Infrared , Water , X-Ray Diffraction , beta-Cyclodextrins/chemistry
3.
Int J Mol Sci ; 23(9)2022 May 09.
Article in English | MEDLINE | ID: covidwho-1847345

ABSTRACT

Fibrosis of extraocular muscles (EOMs) is a marker of end-stage in Graves' orbitopathy (GO). To determine the antifibrotic and anti-inflammatory therapeutic effects and the underlying molecular mechanisms of disulfiram (DSF) on perimysial orbital fibroblasts (pOFs) in a GO model in vitro, primary cultures of pOFs from eight patients with GO and six subjects without GO (NG) were established. CCK-8 and EdU assays, IF, qPCR, WB, three-dimensional collagen gel contraction assays, cell scratch experiments, and ELISAs were performed. After TGF-ß1 stimulation of pOFs, the proliferation rate of the GO group but not the NG group increased significantly. DSF dose-dependently inhibited the proliferation, contraction, and migration of pOFs in the GO group. Additionally, DSF dose-dependently inhibited fibrosis and extracellular matrix production markers (FN1, COL1A1, α-SMA, CTGF) at the mRNA and protein levels. Furthermore, DSF mediates antifibrotic effects on GO pOFs partially through the ERK-Snail signaling pathway. In addition, DSF attenuated HA production and suppressed inflammatory chemokine molecule expression induced by TGF-ß1 in GO pOFs. In this in vitro study, we demonstrate the inhibitory effect of DSF on pOFs fibrosis in GO, HA production, and inflammation. DSF may be a potential drug candidate for preventing and treating tissue fibrosis in GO.


Subject(s)
Graves Ophthalmopathy , Anti-Inflammatory Agents/pharmacology , Cells, Cultured , Disulfiram/metabolism , Disulfiram/pharmacology , Fibroblasts/metabolism , Fibrosis , Graves Ophthalmopathy/drug therapy , Graves Ophthalmopathy/metabolism , Humans , Transforming Growth Factor beta1/metabolism
4.
Eur J Pharmacol ; 904: 174143, 2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1487708

ABSTRACT

Disulfiram (DSF) is a well-known anti-alcohol agent that inhibits aldehyde dehydrogenase and results in extreme 'hangover' symptoms when consumed with alcohol. This drug, however, has been suggested as useful in other forms of drug addiction due to its beneficial potential in both drug abuse reduction and withdrawal. However, among other drugs used in alcohol dependence, it carries the greatest risk of pharmacological interactions. Concomitant use of DSF and central nervous system stimulants usually leads to harmful, undesirable effects. To date, there is still limited data regarding the detailed safety profile of DSF as a concomitant drug. In this review article, we outline the current state of knowledge about DSF, its broad pharmacological action, as well as therapeutic effects, with a particular emphasis on the molecular understanding of its potential pharmacodynamic interactions with common addictive substances (e.g., alcohol, cocaine, cannabinoids, opioids) supported by relevant examples.


Subject(s)
Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Acetaldehyde Dehydrogenase Inhibitors/therapeutic use , Disulfiram/pharmacology , Disulfiram/therapeutic use , Substance-Related Disorders/drug therapy , Alcohol Drinking/prevention & control , Alcoholism/drug therapy , Animals , Disulfiram/adverse effects , Drug Interactions , Humans
5.
Acta Pharmacol Sin ; 42(11): 1913-1920, 2021 11.
Article in English | MEDLINE | ID: covidwho-1437673

ABSTRACT

Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.


Subject(s)
COVID-19 Drug Treatment , COVID-19 , Colitis, Ulcerative , Disulfiram/pharmacokinetics , Lactoferrin , Systemic Inflammatory Response Syndrome , Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Biomimetic Materials/pharmacology , COVID-19/immunology , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/immunology , Disease Models, Animal , Disulfiram/pharmacology , Drug Carriers/pharmacology , Humans , Immunosuppressive Agents/pharmacology , Lactoferrin/metabolism , Lactoferrin/pharmacology , Lipopolysaccharides/immunology , Macrophages/drug effects , Macrophages/immunology , Mice , Mice, Inbred C57BL , Nanoparticles/therapeutic use , Pyroptosis/drug effects , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , Treatment Outcome
6.
Biophys Chem ; 276: 106610, 2021 09.
Article in English | MEDLINE | ID: covidwho-1252522

ABSTRACT

In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and SARS-CoV-2. Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses. The pandemic of SARS-CoV-2 reminds us the urgency to search new drugs with totally different mechanism that may target the weaknesses specific to coronaviruses. Herein, we disclose a computational evaluation of targeted oxidation strategy (TOS) for potential inhibition of SARS-CoV-2 by disulfiram, a 70-year-old anti-alcoholism drug, and predict a multiple-target mechanism. A preliminary list of promising TOS drug candidates targeting the two thiol proteases of SARS-CoV-2 are proposed upon virtual screening of 32,143 disulfides.


Subject(s)
Alcohol Deterrents/chemistry , Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Disulfiram/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Alcohol Deterrents/pharmacology , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/metabolism , Disulfiram/pharmacology , Drug Repositioning , Gene Expression , Humans , Kinetics , Molecular Docking Simulation , Oxidation-Reduction , Protease Inhibitors/pharmacology , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Quantum Theory , SARS-CoV-2/enzymology , Substrate Specificity , Thermodynamics , COVID-19 Drug Treatment
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