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1.
Viruses ; 12(5)2020 05 24.
Article in English | MEDLINE | ID: covidwho-1726014

ABSTRACT

Feline infectious peritonitis (FIP) is a viral disease with a high morbidity and mortality by the FIP virus (FIPV, virulent feline coronavirus). Several antiviral drugs for FIP have been identified, but many of these are expensive and not available in veterinary medicine. Hydroxychloroquine (HCQ) is a drug approved by several countries to treat malaria and immune-mediated diseases in humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2, dengue virus) have been confirmed. We investigated whether HCQ in association with interferon-ω (IFN-ω) is effective for FIPV in vitro. A total of 100 µM of HCQ significantly inhibited the replication of types I and II FIPV. Interestingly, the combination of 100 µM of HCQ and 104 U/mL of recombinant feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral activity against type I FIPV infection. Our study suggested that HCQ and rfIFN-ω are applicable for treatment of FIP. Further clinical studies are needed to verify the combination of HCQ and rIFN-ω will be effective and safe treatment for cats with FIP.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus, Feline/drug effects , Hydroxychloroquine/pharmacology , Interferon Type I/pharmacology , Analysis of Variance , Animals , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Cats , Cell Line/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Coronavirus, Feline/pathogenicity , Drug Combinations , Feline Infectious Peritonitis/drug therapy , Feline Infectious Peritonitis/virology , Fluorescent Antibody Technique/veterinary , Hydroxychloroquine/therapeutic use , Hydroxychloroquine/toxicity , Interferon Type I/therapeutic use , Interferon Type I/toxicity , Virulence
2.
Arthritis Res Ther ; 24(1): 6, 2022 01 03.
Article in English | MEDLINE | ID: covidwho-1590005

ABSTRACT

BACKGROUND: Hydroxychloroquine (HCQ) has been recommended as a basic treatment for lupus nephritis (LN) during this decade based on its ability to improve LN-related renal immune-mediated inflammatory lesions. As a classical lysosomal inhibitor, HCQ may inhibit lysosomal degradation and disrupt protective autophagy in proximal tubular epithelial cells (PTECs). Therefore, the final renal effects of HCQ on LN need to be clarified. METHOD: HCQ was administered on spontaneous female MRL/lpr LN mice with severe proteinuria daily for 4 weeks. Moreover, the MRL/lpr mice with proteinuric LN were subjected to cisplatin-induced or unilateral ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) after 2 weeks of HCQ preadministration. RESULTS: As expected, HCQ treatment increased the survival ratio and downregulated the levels of serum creatinine in the mice with LN, ameliorated renal lesions, and inhibited renal interstitial inflammation. Unexpectedly, HCQ preadministration significantly increased susceptibility to and delayed the recovery of AKI complicated by LN, as demonstrated by an increase in PTEC apoptosis and expression of the tubular injury marker KIM-1 as well as the retardation of PTEC replenishment. HCQ preadministration suppressed the proliferation of PTECs by arresting cells in G1/S phase and upregulated the expression of cell cycle inhibitors. Furthermore, HCQ preadministration disrupted the PTEC autophagy-lysosomal pathway and accelerated PTEC senescence. CONCLUSION: HCQ treatment may increase susceptibility and delay the recovery of AKI complicated by LN despite its ability to improve LN-related renal immune-mediated inflammatory lesions. The probable mechanism involves accelerated apoptosis and inhibited proliferation of PTECs via autophagy-lysosomal pathway disruption and senescence promotion.


Subject(s)
Acute Kidney Injury , Lupus Nephritis , Acute Kidney Injury/chemically induced , Animals , Female , Hydroxychloroquine/pharmacology , Kidney/pathology , Mice , Mice, Inbred MRL lpr
3.
Int J Mol Sci ; 23(3)2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1674670

ABSTRACT

This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood-brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of -8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = -8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.


Subject(s)
Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Tetraoxanes/pharmacology , Antiviral Agents/pharmacology , Binding Sites , COVID-19/drug therapy , Computational Biology/methods , Drug Evaluation, Preclinical/methods , Humans , Hydroxychloroquine/analogs & derivatives , Molecular Docking Simulation/methods , Molecular Dynamics Simulation , Protease Inhibitors/pharmacology , Protein Binding/drug effects , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism
4.
Sci Rep ; 12(1): 1075, 2022 01 20.
Article in English | MEDLINE | ID: covidwho-1642005

ABSTRACT

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management.


Subject(s)
Arrhythmias, Cardiac , Azithromycin/pharmacology , COVID-19 , Hydroxychloroquine/pharmacology , Interleukin-6/metabolism , SARS-CoV-2/metabolism , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/prevention & control , COVID-19/complications , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/physiopathology , Female , Guinea Pigs , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/physiopathology , Interleukin-6/antagonists & inhibitors , Male
5.
Front Biosci (Landmark Ed) ; 26(12): 1493-1502, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1614662

ABSTRACT

BACKGROUND: Despite the fact that the clinical efficacy of hydroxychloroquine is still controversial, it has been demonstrated in vitro to control SARS-CoV-2 multiplication on Vero E6 cells. In this study, we tested the possibility that some patients with prolonged virus excretion could be infected by less susceptible strains. METHOD: Using a high-content screening method, we screened 30 different selected isolates of SARS-CoV-2 from different patients who received azithromycin ± hydroxychloroquine. We focused on patients with viral persistence, i.e., positive virus detection in a nasopharyngeal sample ≥10 days, and who were tested during two French epidemic waves, late winter-spring of 2020 and the summer of 2020. Dose-response curves in single-molecule assays with hydroxychloroquine were created for isolates with suspected reduced susceptibility. Genome clustering was performed for all isolates. RESULTS: Of 30 tested strains, three were detected as replicating in the presence of azithromycin + hydroxychloroquine, each at 5 µM. The dose-response model showed a decrease in susceptibility of these three strains to hydroxychloroquine. Whole genome sequencing revealed that these three strains are all from the second epidemic wave and two cluster with isolates from Africa. CONCLUSIONS: Reduced susceptibility to hydroxychloroquine was not associated with viral persistence in naso-pharyngeal samples. Rather, it was associated with occurring during the second epidemic wave, which began in the summer and with strains clustering with those with a common genotype in Africa, where hydroxychloroquine was the most widely used.


Subject(s)
COVID-19 , Hydroxychloroquine , Azithromycin/pharmacology , COVID-19/drug therapy , Humans , Hydroxychloroquine/pharmacology , SARS-CoV-2
6.
Front Immunol ; 12: 796855, 2021.
Article in English | MEDLINE | ID: covidwho-1607033

ABSTRACT

Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-ß-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.


Subject(s)
COVID-19/metabolism , Cholesterol/metabolism , Membrane Microdomains/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/prevention & control , COVID-19/virology , Humans , Hydroxychloroquine/pharmacology , Protein Binding/drug effects , SARS-CoV-2/physiology , Virus Internalization/drug effects , beta-Cyclodextrins/pharmacology
7.
Int J Mol Sci ; 22(24)2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1580692

ABSTRACT

Although blood-heart-barrier (BHB) leakage is the hallmark of congestive (cardio-pulmonary) heart failure (CHF), the primary cause of death in elderly, and during viral myocarditis resulting from the novel coronavirus variants such as the severe acute respiratory syndrome novel corona virus 2 (SARS-CoV-2) known as COVID-19, the mechanism is unclear. The goal of this project is to determine the mechanism of the BHB in CHF. Endocardial endothelium (EE) is the BHB against leakage of blood from endocardium to the interstitium; however, this BHB is broken during CHF. Previous studies from our laboratory, and others have shown a robust activation of matrix metalloproteinase-9 (MMP-9) during CHF. MMP-9 degrades the connexins leading to EE dysfunction. We demonstrated juxtacrine coupling of EE with myocyte and mitochondria (Mito) but how it works still remains at large. To test whether activation of MMP-9 causes EE barrier dysfunction, we hypothesized that if that were the case then treatment with hydroxychloroquine (HCQ) could, in fact, inhibit MMP-9, and thus preserve the EE barrier/juxtacrine signaling, and synchronous endothelial-myocyte coupling. To determine this, CHF was created by aorta-vena cava fistula (AVF) employing the mouse as a model system. The sham, and AVF mice were treated with HCQ. Cardiac hypertrophy, tissue remodeling-induced mitochondrial-myocyte, and endothelial-myocyte contractions were measured. Microvascular leakage was measured using FITC-albumin conjugate. The cardiac function was measured by echocardiography (Echo). Results suggest that MMP-9 activation, endocardial endothelial leakage, endothelial-myocyte (E-M) uncoupling, dyssynchronous mitochondrial fusion-fission (Mfn2/Drp1 ratio), and mito-myocyte uncoupling in the AVF heart failure were found to be rampant; however, treatment with HCQ successfully mitigated some of the deleterious cardiac alterations during CHF. The findings have direct relevance to the gamut of cardiac manifestations, and the resultant phenotypes arising from the ongoing complications of COVID-19 in human subjects.


Subject(s)
COVID-19/complications , Heart Failure/metabolism , Heart/virology , Animals , Blood/virology , Blood Physiological Phenomena/immunology , COVID-19/physiopathology , Cardiomegaly/metabolism , Cardiovascular Diseases/metabolism , Cardiovascular Physiological Phenomena/immunology , Disease Models, Animal , Endothelium/metabolism , Heart/physiopathology , Heart Failure/virology , Hydroxychloroquine/pharmacology , Male , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Muscle Cells/metabolism , Myocardium/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Ventricular Remodeling/physiology
8.
Molecules ; 26(24)2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1572567

ABSTRACT

COVID-19 is the name of the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that occurred in 2019. The virus-host-specific interactions, molecular targets on host cell deaths, and the involved signaling are crucial issues, which become potential targets for treatment. Spike protein, angiotensin-converting enzyme 2 (ACE2), cathepsin L-cysteine peptidase, transmembrane protease serine 2 (TMPRSS2), nonstructural protein 1 (Nsp1), open reading frame 7a (ORF7a), viral main protease (3C-like protease (3CLpro) or Mpro), RNA dependent RNA polymerase (RdRp) (Nsp12), non-structural protein 13 (Nsp13) helicase, and papain-like proteinase (PLpro) are molecules associated with SARS-CoV infection and propagation. SARS-CoV-2 can induce host cell death via five kinds of regulated cell death, i.e., apoptosis, necroptosis, pyroptosis, autophagy, and PANoptosis. The mechanisms of these cell deaths are well established and can be disrupted by synthetic small molecules or natural products. There are a variety of compounds proven to play roles in the cell death inhibition, such as pan-caspase inhibitor (z-VAD-fmk) for apoptosis, necrostatin-1 for necroptosis, MCC950, a potent and specific inhibitor of the NLRP3 inflammasome in pyroptosis, and chloroquine/hydroxychloroquine, which can mitigate the corresponding cell death pathways. However, NF-κB signaling is another critical anti-apoptotic or survival route mediated by SARS-CoV-2. Such signaling promotes viral survival, proliferation, and inflammation by inducing the expression of apoptosis inhibitors such as Bcl-2 and XIAP, as well as cytokines, e.g., TNF. As a result, tiny natural compounds functioning as proteasome inhibitors such as celastrol and curcumin can be used to modify NF-κB signaling, providing a responsible method for treating SARS-CoV-2-infected patients. The natural constituents that aid in inhibiting viral infection, progression, and amplification of coronaviruses are also emphasized, which are in the groups of alkaloids, flavonoids, terpenoids, diarylheptanoids, and anthraquinones. Natural constituents derived from medicinal herbs have anti-inflammatory and antiviral properties, as well as inhibitory effects, on the viral life cycle, including viral entry, replication, assembly, and release of COVID-19 virions. The phytochemicals contain a high potential for COVID-19 treatment. As a result, SARS-CoV-2-infected cell death processes and signaling might be of high efficacy for therapeutic targeting effects and yielding encouraging outcomes.


Subject(s)
COVID-19/drug therapy , Cell Death/drug effects , Drug Discovery/methods , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , Amino Acid Chloromethyl Ketones/pharmacology , Antiviral Agents/pharmacology , Apoptosis/drug effects , Furans/pharmacology , Humans , Hydroxychloroquine/pharmacology , Imidazoles/pharmacology , Indenes/pharmacology , Indoles/pharmacology , Necroptosis/drug effects , Phytochemicals/pharmacology , Pyroptosis/drug effects , SARS-CoV-2/metabolism , Signal Transduction/drug effects , Sulfonamides/pharmacology , Viral Proteins/antagonists & inhibitors
9.
Eur J Pharmacol ; 915: 174670, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1549763

ABSTRACT

Hydroxychloroquine (HCQ) is a derivative of the antimalaria drug chloroquine primarily prescribed for autoimmune diseases. Recent attempts to repurpose HCQ in the treatment of corona virus disease 2019 has raised concerns because of its propensity to prolong the QT-segment on the electrocardiogram, an effect associated with increased pro-arrhythmic risk. Since chirality can affect drug pharmacological properties, we have evaluated the functional effects of the R(-) and S(+) enantiomers of HCQ on six ion channels contributing to the cardiac action potential and on electrophysiological parameters of isolated Purkinje fibers. We found that R(-)HCQ and S(+)HCQ block human Kir2.1 and hERG potassium channels in the 1 µM-100 µM range with a 2-4 fold enantiomeric separation. NaV1.5 sodium currents and CaV1.2 calcium currents, as well as KV4.3 and KV7.1 potassium currents remained unaffected at up to 90 µM. In rabbit Purkinje fibers, R(-)HCQ prominently depolarized the membrane resting potential, inducing autogenic activity at 10 µM and 30 µM, while S(+)HCQ primarily increased the action potential duration, inducing occasional early afterdepolarization at these concentrations. These data suggest that both enantiomers of HCQ can alter cardiac tissue electrophysiology at concentrations above their plasmatic levels at therapeutic doses, and that chirality does not substantially influence their arrhythmogenic potential in vitro.


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Heart/drug effects , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Ion Channels/drug effects , Action Potentials/drug effects , Animals , Arrhythmias, Cardiac/chemically induced , Electrocardiography , Electrophysiologic Techniques, Cardiac , Ether-A-Go-Go Potassium Channels , Humans , Membrane Potentials/drug effects , Patch-Clamp Techniques , Purkinje Fibers/drug effects , Rabbits , Stereoisomerism
10.
Antiviral Res ; 197: 105212, 2022 01.
Article in English | MEDLINE | ID: covidwho-1530602

ABSTRACT

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.


Subject(s)
Anti-Infective Agents/pharmacology , Azithromycin/pharmacology , COVID-19/drug therapy , Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Animals , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/therapeutic use , Azithromycin/administration & dosage , Azithromycin/pharmacokinetics , Azithromycin/therapeutic use , Bronchi/cytology , Bronchi/virology , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/therapeutic use , Lung/pathology , Mesocricetus , Middle Aged , Plasma/virology , Real-Time Polymerase Chain Reaction , Vero Cells
11.
Bioorg Med Chem ; 53: 116523, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1525708

ABSTRACT

Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir's limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 µM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Chlorocebus aethiops , Drug Repositioning , Female , Hydroxychloroquine/chemical synthesis , Hydroxychloroquine/toxicity , Male , Mice , Microbial Sensitivity Tests , Stereoisomerism , Vero Cells
12.
J Sep Sci ; 45(2): 456-467, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1499288

ABSTRACT

Chloroquine and hydroxychloroquine have been studied since the early clinical treatment of SARS-CoV-2 outbreak. Considering these two chiral drugs are currently in use as the racemate, high-expression angiotensin-converting enzyme 2 cell membrane chromatography was established for investigating the differences of two paired enantiomers binding to angiotensin-converting enzyme 2 receptor. Molecular docking assay and detection of SARS-CoV-2 spike pseudotyped virus entry into angiotensin-converting enzyme 2-HEK293T cells were also conducted for further investigation. Results showed that each single enantiomer could bind well to angiotensin-converting enzyme 2, but there were differences between the paired enantiomers and corresponding racemate in frontal analysis. R-Chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine. Moreover, each single enantiomer was proved effective compared with the control group; compared with S-chloroquine or the racemate, R-chloroquine showed better inhibitory effects at the same concentration. As for hydroxychloroquine, R-hydroxychloroquine showed better inhibitory effects than S-hydroxychloroquine, but it slightly worse than the racemate. In conclusion, R-chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability and inhibitory effects compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine (racemate), while the effect of preventing SARS-CoV-2 pseudovirus from entering cells was weaker than R-hydroxychloroquine/hydroxychloroquine (racemate).


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/drug effects , Chloroquine/chemistry , Chloroquine/pharmacology , Chromatography, High Pressure Liquid/methods , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Cell Membrane/chemistry , Cell Membrane/drug effects , Cell Membrane/virology , HEK293 Cells , Humans , In Vitro Techniques , Molecular Docking Simulation , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/chemistry , Receptors, Virus/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Solvents , Stereoisomerism , Virus Internalization
13.
J Cell Biochem ; 123(2): 347-358, 2022 02.
Article in English | MEDLINE | ID: covidwho-1499273

ABSTRACT

As per the World Health Organization report, around 226 844 344 confirmed positive cases and 4 666 334 deaths are reported till September 17, 2021 due to the recent viral outbreak. A novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) is responsible for the associated coronavirus disease (COVID-19), which causes serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to combat the outbreak. Due to the emergency, the drug repurposing approach is being explored for COVID-19. In this study, we attempt to understand the potential mechanism and also the effect of the approved antiviral drugs against the SARS-CoV-2 main protease (Mpro). To understand the mechanism of inhibition of the malaria drug hydroxychloroquine (HCQ) against SARS-CoV-2, we performed molecular interaction studies. The studies revealed that HCQ docked at the active site of the Human ACE2 receptor as a possible way of inhibition. Our in silico analysis revealed that the three drugs Lopinavir, Ritonavir, and Remdesivir showed interaction with the active site residues of Mpro. During molecular dynamics simulation, based on the binding free energy contributions, Lopinavir showed better results than Ritonavir and Remdesivir.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Hydroxychloroquine/pharmacology , Lopinavir/pharmacology , Receptors, Virus/drug effects , Ritonavir/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/physiology , Antiviral Agents/therapeutic use , Binding Sites , Catalytic Domain/drug effects , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/physiology , Datasets as Topic , Drug Repositioning , Energy Transfer , Humans , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Receptors, Virus/physiology , Ritonavir/therapeutic use
14.
J Cell Biochem ; 123(2): 155-160, 2022 02.
Article in English | MEDLINE | ID: covidwho-1473858

ABSTRACT

Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.


Subject(s)
Antiviral Agents/pharmacology , Artesunate/pharmacology , Autophagy/drug effects , COVID-19/drug therapy , Drug Repositioning , Imatinib Mesylate/pharmacology , Infliximab/pharmacology , Pandemics , SARS-CoV-2/drug effects , Antidepressive Agents/pharmacology , Antiviral Agents/therapeutic use , Artesunate/therapeutic use , Chloroquine/pharmacology , Drug Development , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/physiology , Endoplasmic Reticulum/virology , Endosomes/drug effects , Endosomes/virology , Humans , Hydroxychloroquine/pharmacology , Imatinib Mesylate/therapeutic use , Infliximab/therapeutic use , Intracellular Membranes/drug effects , Intracellular Membranes/physiology , Intracellular Membranes/virology , Ivermectin/pharmacology , Macrolides/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Niclosamide/pharmacology , Niclosamide/therapeutic use , RNA, Viral/metabolism , SARS-CoV-2/physiology , Virus Replication
16.
Eur J Immunol ; 52(1): 54-61, 2022 01.
Article in English | MEDLINE | ID: covidwho-1439676

ABSTRACT

Toll-like receptor 7 (TLR7) triggers antiviral immune responses through its capacity to recognize ssRNA. Proteolytic cleavage of TLR7 protein is required for its functional maturation in the endosomal compartment. Structural studies demonstrated that the N- and C-terminal domains of TLR7 are connected and involved in ligand binding after cleavage. Hydroxychloroquine (HCQ), an antimalarial drug, has been studied for its antiviral effects. HCQ increases pH in acidic organelles and has been reported to potently inhibit endosomal TLR activation. Whether HCQ can prevent endogenous TLR7 cleavage in primary immune cells, such as plasmacytoid DCs (pDCs), had never been examined. Here, using a validated anti-TLR7 antibody suitable for biochemical detection of native TLR7 protein, we show that HCQ treatment of fresh PBMCs, CAL-1 leukemic, and primary human pDCs inhibits TLR7 cleavage and results in accumulation of full-length protein. As a consequence, we observe an inhibition of pDC activation in response to TLR7 stimulation with synthetic ligands and viruses including inactivated SARS-CoV2, which we show herein activates pDCs through TLR7-signaling. Together, our finding suggests that the major pathway by which HCQ inhibits ssRNA sensing by pDCs may rely on its capacity to inhibit endosomal acidification and the functional maturation of TLR7 protein.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Hydroxychloroquine/pharmacology , Proteolysis/drug effects , SARS-CoV-2/immunology , Toll-Like Receptor 7/immunology , COVID-19/drug therapy , Cell Line , Endosomes/immunology , Humans
19.
Pharmacol Rep ; 73(6): 1520-1538, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1377631

ABSTRACT

The global spread of COVID-19 has imparted significant economic, medical, and social burdens. Like adults, children are affected by this pandemic. However, milder clinical symptoms are often experienced by them. Only a minimal proportion of the affected patients may develop severe and complicated COVID-19. Supportive treatment is recommended in all patients. Antiviral and immunomodulatory medications are spared for hospitalized children with respiratory distress or severe to critical disease. Up till now, remdesivir is the only USFDA-approved anti-COVID-19 medication indicated in the majority of symptomatic patients with moderate to severe disease. Dexamethasone is solely recommended in patients with respiratory distress maintained on oxygen or ventilatory support. The use of these medications in pediatric patients is founded on evidence deriving from adult studies. No randomized controlled trials (RCTs) involving pediatric COVID-19 patients have assessed these medications' efficacy and safety, among others. Similarly, three novel monoclonal anti-SARS-CoV-2 spike protein antibodies, bamlanivimab, casirivimab and imdevimab, have been recently authorized by the USFDA. Nonetheless, their efficacy has not been demonstrated by multiple RCTs. In this review, we aim to dissect the various potential therapeutics used in children with COVID-19. We aspire to provide a comprehensive review of the available evidence and display the mechanisms of action and the pharmacokinetic properties of the studied therapeutics. Our review offers an efficient and practical guide for treating children with COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Azithromycin/pharmacology , Child , Dexamethasone/pharmacology , Humans , Hydroxychloroquine/pharmacology , Ivermectin/pharmacology , Lopinavir/pharmacology , Oseltamivir/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
20.
Biomed Res Int ; 2021: 6614000, 2021.
Article in English | MEDLINE | ID: covidwho-1327769

ABSTRACT

Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown the ability to inhibit in vitro viral replications of coronaviridae viruses such as SARS-CoV and SARS-CoV-2. However, clinical trial outcomes have been disparate, suggesting that CQ and HCQ antiviral mechanisms are not fully understood. Based on three-dimensional structural similarities between HCQ and the known ACE2 specific inhibitor MLN-4760, we compared their modulation on ACE2 activity. Here we describe, for the first time, in a cell-free in vitro system that HCQ directly and dose-dependently inhibits the activity of recombinant human ACE2, with a potency similar to the MLN-4760. Further analysis suggests that HCQ binds to a noncompetitive site other than the one occupied by MLN-4760. We also determined that the viral spike glycoprotein segment that comprises the RBD segment has no effect on ACE2 activity but unexpectedly was able to partially reverse the inhibition induced by HCQ but not that by MLN-4760. In summary, here we demonstrate the direct inhibitory action of HCQ over the activity of the enzyme ACE2. Then, by determining the activity of ACE2, we reveal that the interaction with the spike protein of SARS-CoV-2 leads to structural changes that at least partially displace the interaction of the said enzyme with HCQ. These results may help to explain why the effectiveness of HCQ in clinical trials has been so variable. Additionally, this knowledge could be used for to develop techniques for the detection of SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents , COVID-19/drug therapy , Hydroxychloroquine , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/metabolism , Hydroxychloroquine/pharmacology , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Leucine/analogs & derivatives , Leucine/chemistry , Leucine/metabolism , Leucine/pharmacology , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
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