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The Journal of Biological Chemistry Mar 2022Lung cancer has the highest mortality among cancers worldwide due to its high incidence and lack of the effective cures. We have previously demonstrated that the...
Lung cancer has the highest mortality among cancers worldwide due to its high incidence and lack of the effective cures. We have previously demonstrated that the membrane ion channel TMEM16A is a potential drug target for the treatment of lung adenocarcinoma and have identified a pocket of inhibitor binding that provides the basis for screening promising new inhibitors. However, conventional drug discovery strategies are lengthy and costly, and the unpredictable side effects lead to a high failure rate in drug development. Therefore, finding new therapeutic directions for already marketed drugs may be a feasible strategy to obtain safe and effective therapeutic drugs. Here, we screened a library of over 1400 Food and Drug Administration-approved drugs through virtual screening and activity testing. We identified a drug candidate, Zafirlukast (ZAF), clinically approved for the treatment of asthma, that could inhibit the TMEM16A channel in a concentration-dependent manner. Molecular dynamics simulations and site-directed mutagenesis experiments showed that ZAF can bind to S387/N533/R535 in the nonselective inhibitor binding pocket, thereby blocking the channel pore. Furthermore, we demonstrate ZAF can target TMEM16A channel to inhibit the proliferation and migration of lung adenocarcinoma LA795 cells. In vivo experiments showed that ZAF can significantly inhibit lung adenocarcinoma tumor growth in mice. Taken together, we identified ZAF as a novel TMEM16A channel inhibitor with excellent anticancer activity, and as such, it represents a promising candidate for future preclinical and clinical studies.
Topics: Adenocarcinoma of Lung; Animals; Anoctamin-1; Chloride Channels; Indoles; Lung Neoplasms; Mice; Phenylcarbamates; Sulfonamides
PubMed: 35176281
DOI: 10.1016/j.jbc.2022.101731 -
Journal of Biomolecular Structure &... Sep 2022The outbreak of Coronavirus infection (COVID-19) has prompted the World Health Organisation (WHO) to declare the outbreak, a Public Health Emergency of International...
The outbreak of Coronavirus infection (COVID-19) has prompted the World Health Organisation (WHO) to declare the outbreak, a Public Health Emergency of International concern. As part of the efforts to discover lead compounds for clinical use, 53 molecules were screened using molecular docking and dynamic simulations (MDS) techniques to identify potential inhibitors of SARS-CoV-2 spike protein (COVID-19 S) and main protease (COVID-19 M) or both. Lopinavir (LPV), nelfinavir (NEF), hydroxychloroquine (HCQ), remdesivir (RDV) and an irreversible inhibitor of SARS-CoV (N3) were used as standard drugs for COVID-19 M, while zafirlukast (ZFK) and cefoperazone (CSP)) as standard drugs for COVID-19 S. After 100ns of MDS, with reference to standard drugs (N3, -52.463 Kcal/mol, NEF, -51.618 Kcal/mol, RDV, -48.780 Kcal/mol, LPV, -46.788 Kcal/mol, DRV, -33.655 Kcal/mol and HCQ, -21.065 Kcal/mol), five molecules, HCR, GRN, C3G, EGCG, and K7G were predicted to be promising inhibitors of COVID-19 M with binding energies of -53.877kcal/mol, -50.653 Kcal/mol, -48.600kcal/mol, -47.798kcal/mol and -46.902kcal/mol, respectively. These lead molecules were then docked at receptor-binding domain (RBD) of COVID-19 S to examine their inhibitory effects. C3G, GRN and K7G exhibited higher binding energies of -42.310kcal/mol, -32.210kcal/mol, -26.922kcal/mol than the recorded values for the reference drugs (CSP, -35.509kcal/mol, ZFK, -24.242kcal/mol), respectively. The results of the binding energy and structural analyses from this study revealed that C3G, GRN and K7G could serve as potential dual inhibitors of COVID-19 S and COVID-19 M, while HCR and EGCG would be inhibitors of COVID-19 Mpro.Communicated by Ramaswamy H. Sarma.
Topics: Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Peptide Hydrolases; Protease Inhibitors; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 33590806
DOI: 10.1080/07391102.2021.1886993 -
European Journal of Pharmaceutics and... Dec 2023Intestinal drug solubility is a key parameter controlling absorption after the administration of a solid oral dosage form. The ability to measure fed state solubility in...
Intestinal drug solubility is a key parameter controlling absorption after the administration of a solid oral dosage form. The ability to measure fed state solubility in vitro is limited and multiple simulated intestinal fluid recipes have been developed but with no consensus which is optimal. This study has utilised nine bioequivalent simulated fed intestinal media recipes that cover over 90% of the compositional variability of sampled fed human intestinal fluid. The solubility of 24 drugs (Acidic; furosemide, ibuprofen, indomethacin, mefenamic acid, naproxen, phenytoin, piroxicam, valsartan, zafirlukast: Basic; aprepitant, atazanavir, bromocriptine, carvedilol, dipyridamole, posaconazole, tadalafil: Neutral; acyclovir, carbamazepine, felodipine, fenofibrate, griseofulvin, itraconazole, paracetamol, probucol) has been assessed to determine if structured solubility behaviour is present. The measured solubility behaviour can be split into four categories and is consistent with drug physicochemical properties and previous solubility studies. For acidic drugs (category 1) solubility is controlled by media pH and the lowest and highest pH media identify the lowest and highest solubility in 90% of cases. For weakly acidic, basic and neutral drugs (category 2) solubility is controlled by media pH and total amphiphile concentration (TAC), a consistent solubility pattern is evident with variation related to individual drug media component interactions. The lowest and highest pH × TAC media identify the lowest and highest solubility in 70% and 90% of cases respectively. Four drugs, which are non-ionised in the media systems (category 3), have been identified with a very narrow solubility range, indicating minimal impact of the simulated media on solubility. Three drugs exhibit solubility behaviour that is not consistent with the remainder (category 4). The results indicate that the use of two bioequivalent fed intestinal media from the original nine will identify in vitro the maximum and minimum solubility values for the majority of drugs and due to the media derivation this is probably applicable in vivo. When combined with a previous fasted study, this introduces interesting possibilities to measure a solubility range in vitro that can provide Quality by Design based decisions to rationalise drug and formulation development. Overall this indicates that the multi-dimensional media system is worthy of further investigation as in vitro tool to assess fed intestinal solubility.
Topics: Humans; Solubility; Hydrogen-Ion Concentration; Intestines; Pharmaceutical Preparations; Indomethacin; Intestinal Absorption
PubMed: 37890541
DOI: 10.1016/j.ejpb.2023.10.017 -
Antimicrobial Agents and Chemotherapy May 2013The mycobacterial nucleoid-associated protein Lsr2 is a DNA-bridging protein that plays a role in condensation and structural organization of the genome and acts as a...
The mycobacterial nucleoid-associated protein Lsr2 is a DNA-bridging protein that plays a role in condensation and structural organization of the genome and acts as a global repressor of gene transcription. Here we describe experiments demonstrating that zafirlukast inhibits the complexation between Lsr2 and DNA in vitro. Zafirlukast is shown to inhibit growth in two different species of mycobacteria tested but exhibits no growth inhibition of Escherichia coli. The Lsr2 inhibitory activity is reflected in vivo as determined by monitoring of transcription levels in Mycobacterium tuberculosis. These data suggest that zafirlukast inhibits Lsr2 function in vivo, promoting dysregulation of the expression of an array of genes typically bound by Lsr2 and hindering growth. Since zafirlukast likely operates by a mechanism distinct from current M. tuberculosis drugs and is currently used as a prophylactic treatment for asthma, it offers an intriguing lead for development of new treatments for tuberculosis.
Topics: Anti-Asthmatic Agents; Antitubercular Agents; DNA, Bacterial; DNA-Binding Proteins; Drug Repositioning; Escherichia coli; Gene Expression Regulation, Bacterial; Indoles; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenylcarbamates; Protein Binding; Species Specificity; Sulfonamides; Tosyl Compounds; Transcription, Genetic
PubMed: 23439641
DOI: 10.1128/AAC.02407-12 -
Drug Design, Development and Therapy 2018Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for...
BACKGROUND
Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for its postulated 5-LO inhibitory activity along with a Cys-LT receptor antagonist zafirlukast (ZFL) against inflammatory response and tissue injury in mice.
MATERIALS AND METHODS
The spinal injury was induced by two-level laminectomy of T6 and T7 vertebrae. The inflammation was assessed by histology, inflammatory mediators by enzyme-linked immunosorbent assay, apoptosis by Annexin-V, FAS staining, terminal deoxynucleoti-dyltransferase-mediated UTP end labeling (TUNEL) assay and expression of Bax and Bcl-2 by Western blot. Effect on motor recovery of hind limbs was evaluated for 10 days postinjury.
RESULTS
The spinal injury resulted in tissue damage, apoptosis, edema, infiltration of neutrophils with increased expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The spinal tissue showed elevated levels of prostaglandin E (PGE2), and LTB and increased phosphorylation of injured extracellular signal-regulated kinase-1/2 (ERK1/2). The PHP, ZFL and combination decreased inflammation, tissue injury and infiltration of neutrophils. Treatment also decreased the levels of PGE, phosphorylation of extracellular signal-regulated kinase-1/2 (pERK 1/2), LT, TNF-α and COX-2 with a marked reduction in apoptosis and improved the motor function.
CONCLUSION
The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL.
Topics: Animals; Apoptosis; Drug Therapy, Combination; Indoles; Leukotriene Antagonists; Lipoxygenase Inhibitors; Male; Mice; Neutrophil Infiltration; Perylene; Phenylcarbamates; Proto-Oncogene Proteins c-bcl-2; Spinal Cord Injuries; Sulfonamides; Tosyl Compounds; Tumor Necrosis Factor-alpha
PubMed: 30122897
DOI: 10.2147/DDDT.S154814 -
Respiratory Medicine Jun 1998
Review
Topics: Acetates; Asthma; Bronchi; Cyclopropanes; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Leukotriene D4; Lipoxygenase Inhibitors; Membrane Proteins; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Rhinitis; Sinusitis; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 9850362
DOI: 10.1016/s0954-6111(98)90380-8 -
The Cochrane Database of Systematic... 2004Anti-leukotriene (AL) agents are being considered as 'add-on' therapy to inhaled corticosteroids (ICS), in chronic asthma. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Anti-leukotriene (AL) agents are being considered as 'add-on' therapy to inhaled corticosteroids (ICS), in chronic asthma.
OBJECTIVES
To examine the safety and efficacy of daily AL plus ICS compared to ICS alone, and determine the corticosteroid-sparing effect of AL when added to ICS in chronic asthma.
SEARCH STRATEGY
We searched MEDLINE, EMBASE, CINAHL (until August 2003), reference lists of review articles and trials, contacted international headquarters of AL manufacturers and looked at American Thoracic Society and European Respiratory Society meeting abstracts (1998 to 2003).
SELECTION CRITERIA
Randomised placebo-controlled trials of asthmatics aged two years and older with at least one month intervention.
DATA COLLECTION AND ANALYSIS
Two reviewers assessed quality and extracted data independently. Trials were grouped by asthma control at baseline (symptomatic or well-controlled) and dose of ICS in the control group (same or double).
MAIN RESULTS
Of 587 citations, 27 (25 adult and 2 paediatric) trials met inclusion criteria. Sixteen trials were published in full-text and 16 trials reported data in a way that allowed meta-analysis. In symptomatic patients, addition of licensed doses of anti-leukotrienes to ICS resulted in a non-significant reduction in the risk of exacerbations requiring systemic steroids: Relative Risk (RR) 0.64; 95% Confidence Interval (CI) 0.38 to 1.07). A modest improvement group difference in PEF was seen (Weighted Mean Difference (WMD) 7.7 L/min; 95% CI 3.6 to 11.8 L/min) together with decrease in use of rescue short-acting beta2-agonist use (WMD 1 puff/week; 95%CI 0.5 to 2). With only 3 trials comparing the use of licensed doses of anti-leukotrienes with increasing the dose of inhaled glucocorticoids, no firm conclusion can be drawn about the equivalence of both treatment options. In ICS-sparing studies of patients who were well controlled at baseline, addition of anti-leukotrienes produced no overall difference in dose of inhaled glucocorticoids (WMD -21 mcg/d, 95%CI -65, 23 mcg/d), but it was associated with fewer withdrawals due to poor asthma control (RR 0.63, 95% CI 0.42 to 0.95).
REVIEWERS' CONCLUSIONS
The addition of licensed doses of anti-leukotrienes to add-on therapy to inhaled glucocorticoids brings modest improvement in lung function. Although addition of anti-leukotrienes to inhaled glucocorticoids appears comparable to increasing the dose of inhaled steroids, the power of the review is insufficient to confirm the equivalence of both treatment options. Addition of anti-leukotrienes is associated with superior asthma control after glucocorticoid tapering; although the glucocorticoid-sparing effect cannot be quantified at present, it appears modest.
Topics: Administration, Inhalation; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Chronic Disease; Drug Therapy, Combination; Humans; Leukotriene Antagonists; Steroids
PubMed: 15106191
DOI: 10.1002/14651858.CD003133.pub2 -
FASEB Journal : Official Publication of... May 2023Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently...
Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian cancer, where the rate of rise of CA-125 was significantly reduced following treatment with zafirlukast, while no severe adverse events were reported. Thiol isomerase inhibition with zafirlukast represents a novel, well-tolerated therapeutic in the treatment of ovarian cancer.
Topics: Animals; Female; Humans; Mice; Blood Platelets; Indoles; Ovarian Neoplasms; Phenylcarbamates; Sulfhydryl Compounds
PubMed: 37043381
DOI: 10.1096/fj.202201952R -
Journal of Negative Results in... May 2008The potential for tolerance to develop to zafirlukast, a cysteinyl leukotriene (CysLT) receptor antagonist (LRA) in persistent asthma, has not been specifically examined.
BACKGROUND
The potential for tolerance to develop to zafirlukast, a cysteinyl leukotriene (CysLT) receptor antagonist (LRA) in persistent asthma, has not been specifically examined.
OBJECTIVE
To look for any evidence of tolerance and potential for short-term clinical worsening on LRA withdrawal. Outcome measures included changes in; airway hyperresponsiveness to inhaled methacholine (PD20FEV1), daily symptoms and peak expiratory flows (PEF), sputum and blood cell profiles, sputum CysLT and prostaglandin (PG)E2 and exhaled nitric oxide (eNO) levels.
METHODS
A double blind, placebo-controlled study of zafirlukast, 20 mg twice daily over 12 weeks in 21 asthmatics taking beta2-agonists only (Group I), and 24 subjects treated with ICS (Group II).
RESULTS
In Group I, zafirlukast significantly improved morning PEF and FEV1compared to placebo (p < 0.01), and reduced morning waking with asthma from baseline after two weeks (p < 0.05). Similarly in Group II, FEV1 improved compared to placebo (p < 0.05), and there were early within-treatment group improvements in morning PEF, beta2-agonist use and asthma severity scores (p < 0.05). However, most improvements with zafirlukast in Group I and to a lesser extent in Group II deteriorated toward baseline values over 12 weeks. In both groups, one week following zafirlukast withdrawal there were significant deteriorations in morning and evening PEFs and FEV1 compared with placebo (p < or = 0.05) and increased nocturnal awakenings in Group II (p < 0.05). There were no changes in PD20FEV1, sputum CysLT concentrations or exhaled nitric oxide (eNO) levels. However, blood neutrophils significantly increased in both groups following zafirlukast withdrawal compared to placebo (p = 0.007).
CONCLUSION
Tolerance appears to develop to zafirlukast and there is rebound clinical deterioration on drug withdrawal, accompanied by a blood neutrophilia.
Topics: Adult; Aged; Asthma; Dinoprostone; Double-Blind Method; Female; Humans; Indoles; Leukotriene Antagonists; Male; Methacholine Chloride; Middle Aged; Nitric Oxide; Peak Expiratory Flow Rate; Phenylcarbamates; Placebos; Receptors, Adrenergic, beta-2; Sulfonamides; Tosyl Compounds
PubMed: 18489783
DOI: 10.1186/1477-5751-7-3