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1.
Int Immunopharmacol ; 109: 108805, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1814595

ABSTRACT

Pulmonary vascular endothelial dysfunction is a key pathogenic mechanism in acute respiratory distress syndrome (ARDS), resulting in fibrosis in lung tissues, including in the context of COVID-19. Pirfenidone (PFD) has become a novel therapeutic agent for treating idiopathic pulmonary fibrosis (IPF) and can improve lung function, inhibit fibrosis and inhibit inflammation. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play a crucial role in various respiratory diseases. However, the role of PFD in the course of EndMT in LPS-induced ARDS remains poorly understood. The purpose of this study was to explore the anti-EndMT effects of PFD on pulmonary fibrosis after LPS-induced ARDS. First, we determined that PFD significantly reduced LPS-induced ARDS, as shown by significant pathological alterations, and alleviated the oxidative stress and inflammatory response in vitro and in vivo. Furthermore, PFD decreased pulmonary fibrosis in LPS-induced ARDS by inhibiting EndMT and reduced the expression levels of Hedgehog (HH) pathway target genes, such as Gli1 and α-SMA, after LPS induction. In summary, this study confirmed that inhibiting the HH pathway by PFD could decrease pulmonary fibrosis by downregulating EndMT in LPS-induced ARDS. In conclusion, we demonstrate that PFD is a promising agent to attenuate pulmonary fibrosis following ARDS in the future.


Subject(s)
Hedgehog Proteins , Pulmonary Fibrosis , Pyridones , Respiratory Distress Syndrome , Animals , Hedgehog Proteins/metabolism , Lipopolysaccharides , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pyridones/pharmacology , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/drug therapy , Signal Transduction
2.
Org Lett ; 24(3): 804-808, 2022 01 28.
Article in English | MEDLINE | ID: covidwho-1632912

ABSTRACT

A chemical investigation of the filamentous fungus Aspergillus californicus led to the isolation of a polyketide-nonribosomal peptide hybrid, calipyridone A (1). A putative biosynthetic gene cluster cpd for production of 1 was next identified by genome mining. The role of the cpd cluster in the production of 1 was confirmed by multiple gene deletion experiments in the host strain as well as by heterologous expression of the hybrid gene cpdA inAspergillus oryzae. Moreover, chemical analyses of the mutant strains allowed the biosynthesis of 1 to be elucidated. The results indicate that the generation of the 2-pyridone moiety of 1 via nucleophilic attack of the iminol nitrogen to the carbonyl carbon is different from the biosynthesis of other fungal 2-pyridone products through P450-catalyzed tetramic acid ring expansions. In addition, two biogenetic intermediates, calipyridones B and C, showed modest inhibition effects on the plaque-forming ability of SARS-CoV-2.


Subject(s)
Aspergillus/metabolism , Pyridones/metabolism , Aspergillus oryzae/metabolism , COVID-19/drug therapy , Cytochrome P-450 Enzyme System/metabolism , Gene Deletion , Humans , Multigene Family/genetics , Polyketides/metabolism , Polyketides/pharmacology , Pyridones/pharmacology , Pyrrolidinones/metabolism , Pyrrolidinones/pharmacology , SARS-CoV-2/drug effects
3.
Diabetes Metab Syndr ; 15(6): 102328, 2021.
Article in English | MEDLINE | ID: covidwho-1487693

ABSTRACT

BACKGROUND AND AIMS: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS: AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Benzothiazoles/therapeutic use , COVID-19/drug therapy , Pyrazines/therapeutic use , Pyridones/therapeutic use , Registries , Aged , Benzothiazoles/pharmacology , COVID-19/complications , COVID-19/mortality , Diabetes Complications/drug therapy , Female , Humans , Hypertension/complications , Inpatients , Male , Middle Aged , New York/epidemiology , Pilot Projects , Prospective Studies , Pyrazines/pharmacology , Pyridones/pharmacology
4.
Viruses ; 13(9)2021 09 12.
Article in English | MEDLINE | ID: covidwho-1411086

ABSTRACT

Our therapeutic arsenal against viruses is very limited and the current pandemic of SARS-CoV-2 highlights the critical need for effective antivirals against emerging coronaviruses. Cellular assays allowing a precise quantification of viral replication in high-throughput experimental settings are essential to the screening of chemical libraries and the selection of best antiviral chemical structures. To develop a reporting system for SARS-CoV-2 infection, we generated cell lines expressing a firefly luciferase maintained in an inactive form by a consensus cleavage site for the viral protease 3CLPro of coronaviruses, so that the luminescent biosensor is turned on upon 3CLPro expression or SARS-CoV-2 infection. This cellular assay was used to screen a metabolism-oriented library of 492 compounds to identify metabolic vulnerabilities of coronaviruses for developing innovative therapeutic strategies. In agreement with recent reports, inhibitors of pyrimidine biosynthesis were found to prevent SARS-CoV-2 replication. Among the top hits, we also identified the NADPH oxidase (NOX) inhibitor Setanaxib. The anti-SARS-CoV-2 activity of Setanaxib was further confirmed using ACE2-expressing human pulmonary cells Beas2B as well as human primary nasal epithelial cells. Altogether, these results validate our cell-based functional assay and the interest of screening libraries of different origins to identify inhibitors of SARS-CoV-2 for drug repurposing or development.


Subject(s)
Antiviral Agents/isolation & purification , Biosensing Techniques/methods , Coronavirus 3C Proteases/metabolism , SARS-CoV-2/physiology , Virus Replication , Animals , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Drug Discovery , Drug Evaluation, Preclinical , Enzyme Activation , HEK293 Cells , Humans , Luciferases, Firefly/metabolism , Nasal Mucosa/virology , Pyrazolones/pharmacology , Pyridones/pharmacology , SARS-CoV-2/metabolism , Vero Cells , Virus Internalization/drug effects , Virus Replication/drug effects
5.
Viruses ; 13(8)2021 08 11.
Article in English | MEDLINE | ID: covidwho-1355046

ABSTRACT

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.


Subject(s)
Antiviral Agents/pharmacology , Benzothiazoles/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyridones/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , SARS-CoV-2/enzymology , SARS-CoV-2/physiology
6.
Antiviral Res ; 194: 105158, 2021 10.
Article in English | MEDLINE | ID: covidwho-1340541

ABSTRACT

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors. Following this meeting and review of the current literature, this article is intended to summarize current knowledge regarding the clinical impact of resistance to polymerase inhibitors and approaches for surveillance and methods for laboratory evaluation of resistance, both in vitro and in animal models. We highlight limitations and gaps in current knowledge and suggest some strategies for addressing these gaps, including the need for additional clinical studies of influenza antiviral drug combinations. Lessons learned from influenza resistance monitoring may also be helpful for establishing future drug susceptibility surveillance and testing for SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , Influenza, Human/drug therapy , Animals , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Dibenzothiepins/pharmacology , Drug Resistance, Viral , Enzyme Inhibitors/pharmacology , Humans , Influenza, Human/virology , Knowledge , Morpholines/pharmacology , Neuraminidase/therapeutic use , Oseltamivir/pharmacology , Pyridones/pharmacology , SARS-CoV-2/drug effects , Triazines/pharmacology , Virus Replication/drug effects , Zanamivir/pharmacology
7.
Comb Chem High Throughput Screen ; 24(3): 441-454, 2021.
Article in English | MEDLINE | ID: covidwho-1102440

ABSTRACT

BACKGROUND: Coronavirus Disease 2019 (COVID-19) pandemic continues to threaten patients, societies and healthcare systems around the world. There is an urgent need to search for possible medications. OBJECTIVE: This article intends to use virtual screening and molecular docking methods to find potential inhibitors from existing drugs that can respond to COVID-19. METHODS: To take part in the current research investigation and to define a potential target drug that may protect the world from the pandemic of corona disease, a virtual screening study of 129 approved drugs was carried out which showed that their metabolic characteristics, dosages used, potential efficacy and side effects are clear as they have been approved for treating existing infections. Especially 12 drugs against chronic hepatitis B virus, 37 against chronic hepatitis C virus, 37 against human immunodeficiency virus, 14 anti-herpesvirus, 11 anti-influenza, and 18 other drugs currently on the market were considered for this study. These drugs were then evaluated using virtual screening and molecular docking studies on the active site of the (SARS-CoV-2) main protease (6lu7). Once the efficacy of the drug is determined, it can be approved for its in vitro and in vivo activity against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can be beneficial for the rapid clinical treatment of patients. These drugs were considered potentially effective against SARS-CoV-2 and those with high molecular docking scores were proposed as novel candidates for repurposing. The N3 inhibitor cocrystallized with protease (6lu7) and the anti-HIV protease inhibitor Lopinavir were used as standards for comparison. RESULTS: The results suggest the effectiveness of Beclabuvir, Nilotinib, Tirilazad, Trametinib and Glecaprevir as potent drugs against SARS-CoV-2 since they tightly bind to its main protease. CONCLUSION: These promising drugs can inhibit the replication of the virus; hence, the repurposing of these compounds is suggested for the treatment of COVID-19. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. However, the assessment of these potential inhibitors as clinical drugs requires further in vivo tests of these drugs.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/metabolism , Drug Evaluation, Preclinical/methods , SARS-CoV-2/drug effects , Antiviral Agents/metabolism , Binding Sites , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Drug Repositioning , Hepacivirus/drug effects , Influenza A virus/drug effects , Lopinavir/chemistry , Lopinavir/pharmacology , Molecular Docking Simulation , Pyridones/chemistry , Pyridones/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology
8.
J Infect Public Health ; 13(12): 1856-1861, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1023653

ABSTRACT

BACKGROUND: Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for the treatment of COVID-19 till date. Drug repurposing strategy helps to find out the drugs for COVID-19 treatment from existing FDA approved antiviral drugs. In this study, FDA approved small molecule antiviral drugs were repurposed against the major viral proteins of SARS-CoV-2. METHODS: The 3D structures of FDA approved small molecule antiviral drugs were retrieved from PubChem. Virtual screening was performed to find out the lead antiviral drug molecules against main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) using COVID-19 Docking Server. Furthermore, lead molecules were individually docked against protein targets using AutoDock 4.0.1 software and their drug-likeness and ADMET properties were evaluated. RESULTS: Out of 65 FDA approved small molecule antiviral drugs screened, Raltegravir showed highest interaction energy value of -9 kcal/mol against Mpro of SARS-CoV-2 and Indinavir, Tipranavir, and Pibrentasvir exhibited a binding energy value of ≥-8 kcal/mol. Similarly Indinavir showed the highest binding energy of -11.5 kcal/mol against the target protein RdRp and Dolutegravir, Elbasvir, Tipranavir, Taltegravir, Grazoprevir, Daclatasvir, Glecaprevir, Ledipasvir, Pibrentasvir and Velpatasvir showed a binding energy value in range from -8 to -11.2 kcal/mol. The antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine also exhibited good bioavailability and drug-likeness properties. CONCLUSION: This study suggests that the screened small molecule antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine could serve as potential drugs for the treatment of COVID-19 with further validation studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Protease Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Drug Repositioning , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Indinavir/pharmacology , Molecular Docking Simulation , Nitriles/pharmacology , Oxazines/pharmacology , Piperazines/pharmacology , Pyridines/pharmacology , Pyridones/pharmacology , Pyrimidines/pharmacology , Pyrones/pharmacology , Raltegravir Potassium/pharmacology , SARS-CoV-2/enzymology , Sulfonamides/pharmacology
9.
PLoS One ; 15(10): e0240149, 2020.
Article in English | MEDLINE | ID: covidwho-810219

ABSTRACT

From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that in some cases can be complicated by the severe acute respiratory syndrome, sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury. Cost and time efficient approaches to reduce the burthen of the disease are needed. To find potential COVID-19 treatments among the whole arsenal of existing drugs, we combined system biology and artificial intelligence-based approaches. The drug combination of pirfenidone and melatonin has been identified as a candidate treatment that may contribute to reduce the virus infection. Starting from different drug targets the effect of the drugs converges on human proteins with a known role in SARS-CoV-2 infection cycle. Simultaneously, GUILDify v2.0 web server has been used as an alternative method to corroborate the effect of pirfenidone and melatonin against the infection of SARS-CoV-2. We have also predicted a potential therapeutic effect of the drug combination over the respiratory associated pathology, thus tackling at the same time two important issues in COVID-19. These evidences, together with the fact that from a medical point of view both drugs are considered safe and can be combined with the current standard of care treatments for COVID-19 makes this combination very attractive for treating patients at stage II, non-severe symptomatic patients with the presence of virus and those patients who are at risk of developing severe pulmonary complications.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Drug Repositioning , Melatonin/therapeutic use , Pneumonia, Viral/drug therapy , Pyridones/therapeutic use , COVID-19 , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Databases, Pharmaceutical , Furin/metabolism , Humans , Melatonin/pharmacology , Pandemics , Pyridones/pharmacology
10.
Med Hypotheses ; 144: 110005, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-599137

ABSTRACT

Cytokine storm, multiorgan failure, and particularly acute respiratory distress syndrome (ARDS) is the leading cause of mortality and morbidity in patients with COVID-19. A fulminant ARDS kills the majority of COVID-19 victims. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), is a novel anti-fibrotic agent with trivial adverse effects. Pirfenidone is approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF) for patients with mild to moderate disease. Pirfenidone could inhibit apoptosis, downregulate ACE receptors expression, decrease inflammation by several mechanisms and ameliorate oxidative stress and hence protect pneumocytes and other cells from COVID-19 invasion and cytokine storm simultaneously. Based on the pirfenidone mechanism of action and the known pathophysiology of COVID-19, I believe that pirfenidone has the potential for the treatment of COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Pyridones/therapeutic use , Alveolar Epithelial Cells/drug effects , Angiotensin-Converting Enzyme 2/biosynthesis , Angiotensin-Converting Enzyme 2/genetics , Animals , Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , COVID-19/complications , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Disease Models, Animal , Down-Regulation/drug effects , Humans , Lipid Peroxidation/drug effects , Oxidative Stress/drug effects , Pyridones/pharmacology , Receptors, Virus/biosynthesis , Receptors, Virus/genetics
11.
Life Sci ; 256: 117963, 2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-593278

ABSTRACT

The new Coronavirus (SARS-CoV-2) is the cause of a serious infection in the respiratory tract called COVID-19. Structures of the main protease of SARS-CoV-2 (Mpro), responsible for the replication of the virus, have been solved and quickly made available, thus allowing the design of compounds that could interact with this protease and thus to prevent the progression of the disease by avoiding the viral peptide to be cleaved, so that smaller viral proteins can be released into the host's plasma. These structural data are extremely important for in silico design and development of compounds as well, being possible to quick and effectively identify potential inhibitors addressed to such enzyme's structure. Therefore, in order to identify potential inhibitors for Mpro, we used virtual screening approaches based with the structure of the enzyme and two compounds libraries, targeted to SARS-CoV-2, containing compounds with predicted activity against Mpro. In this way, we selected, through docking studies, the 100 top-ranked compounds, which followed to subsequent studies of pharmacokinetic and toxicity predictions. After all the simulations and predictions here performed, we obtained 10 top-ranked compounds that were again in silico analyzed inside the Mpro catalytic site, together some drugs that are being currently investigated for treatment of COVID-19. After proposing and analyzing the interaction modes of these compounds, we submitted one molecule then selected as template to a 2D similarity study in a database containing drugs approved by FDA and we have found and indicated Apixaban as a potential drug for future treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Design , Pneumonia, Viral/drug therapy , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Betacoronavirus/isolation & purification , COVID-19 , Computer Simulation , Coronavirus Infections/virology , Drug Development , Drug Repositioning , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/virology , Pyrazoles/pharmacology , Pyridones/pharmacology , SARS-CoV-2
12.
Eur J Pharmacol ; 882: 173237, 2020 Sep 05.
Article in English | MEDLINE | ID: covidwho-548751

ABSTRACT

Pirfenidone (PFD), a pyridone compound, is well recognized as an antifibrotic agent tailored for the treatment of idiopathic pulmonary fibrosis. Recently, through its anti-inflammatory and anti-oxidant effects, PFD based clinical trial has also been launched for the treatment of coronavirus disease (COVID-19). To what extent this drug can perturb membrane ion currents remains largely unknown. Herein, the exposure to PFD was observed to depress the amplitude of hyperpolarization-activated cation current (Ih) in combination with a considerable slowing in the activation time of the current in pituitary GH3 cells. In the continued presence of ivabradine or zatebradine, subsequent application of PFD decreased Ih amplitude further. The presence of PFD resulted in a leftward shift in Ih activation curve without changes in the gating charge. The addition of this compound also led to a reduction in area of voltage-dependent hysteresis evoked by long-lasting inverted triangular (downsloping and upsloping) ramp pulse. Neither the amplitude of M-type nor erg-mediated K+ current was altered by its presence. In whole-cell potential recordings, addition of PFD reduced the firing frequency, and this effect was accompanied by the depression in the amplitude of sag voltage elicited by hyperpolarizing current stimulus. Overall, this study highlights evidence that PFD is capable of perturbing specific ionic currents, revealing a potential additional impact on functional activities of different excitable cells.


Subject(s)
Cell Membrane/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Pyridones/pharmacology , Animals , Betacoronavirus/metabolism , COVID-19 , Cations/metabolism , Cell Line, Tumor , Cell Membrane/metabolism , Coronavirus Infections/virology , Humans , Ion Channels/drug effects , Ion Channels/metabolism , Ion Transport/drug effects , Membrane Potentials/drug effects , Pandemics , Pneumonia, Viral/virology , Potassium/metabolism , Pyridones/therapeutic use , Rats , SARS-CoV-2 , Sodium/metabolism
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