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1.
J King Saud Univ Sci ; 33(2): 101344, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1386058

ABSTRACT

Camptothetin (CPT) is a quinoline alkaloid originally isolated from the Chinese tree, Camptotheca acuminata Decne. CPT was found to have anticancerous and antiviral properties. Derivatives of natural CPT, including topothecan and irinotecan are used clinically to treat a variety of cancers. Apart from Camptotheca acuminata Decne, CPT production was also found in the perennial plant Ophiorrhiza mungos. In this study we attempted the immobilization of the tissue culture grown callus of Ophiorrhiza mungos for the continuous production of a higher concentration of CPT. As evident from previous studies about the antiviral effects of CPT, we wanted to bioinformatically analyze the binding potential of CPT towards two important proteins of SARS-CoV-2, protease (Mpro) and RNA dependent RNA polymerase (RdRp). Further docking analysis of the CPT against the exterior spike glycoprotein of SARS-CoV-2 was also done to determine their potential interaction. The immobilized callus of Ophiorrhiza mungos produced CPT at a concentration of 420 µg/l by the end of 12 days of growth. The HPLC analysis was done to determine the purity of the CPT synthesized by the immobilization technique. The bioinformatic analysis revealed a higher binding efficiency of CPT and its derivatives, toptecan and irinotecan against Mpro and RdRp. The docking analysis of CPT against the spike glycoprotein of SARS-CoV-2 showed hydrogen bonding with the amino acids at K466 with a bond distance of 2.56A° and K355 with a bond distance of 2.40A°. This finding was of particular importance that other compounds including hydroxychloroquine sulphate, lopinavir and ivermectin could bind with the spike protein only by weak Vander wall bonds and no hydrogen bond formation was noticed. Our studies hence evaluate the efficiency of CPT against SARS-CoV-2, by potentially blocking the interaction of the spike glycoprotein with the angiotensin-converting enzyme 2 (ACE2) receptor found on host cells.

2.
Struct Chem ; : 1-8, 2021 Apr 12.
Article in English | MEDLINE | ID: covidwho-1384542

ABSTRACT

In this study, we have investigated the binding mechanism of two FDA-approved drugs (ivermectin and levosalbutamol) with the spike protein of SARs-CoV-2 using three different computational modeling techniques. Molecular docking results predict that ivermectin shows a large binding affinity for spike protein (- 9.0 kcal/mol) compared to levosalbutamol (- 4.1 kcal/mol). Ivermectin binds with LEU492, GLN493, GLY496, and TRY505 residues in the spike protein through hydrogen bonds and levosalbutamol binds with TYR453 and TYR505 residues. Using density functional theory (DFT) studies, we have calculated the binding energies between ivermectin and levosalbutamol with residues in spike protein which favor their binding are - 22.4 kcal/mol and - 21.08 kcal/mol, respectively. The natural bond orbital (NBO) charge analysis has been performed to estimate the amount of charge transfer that occurred by two drugs during interaction with residues. Molecular dynamics (MD) study confirms the stability of spike protein bound with ivermectin through RMSD and RMSF analyses. Three different computer modeling techniques reveal that ivermectin is more stable than levosalbutamol in the active site of spike protein where hACE2 binds. Therefore, ivermectin can be a suitable inhibitor for SARS-CoV-2 to enter into the human cell through hACE2.

3.
Genes (Basel) ; 11(6)2020 06 26.
Article in English | MEDLINE | ID: covidwho-1280752

ABSTRACT

Ivermectin (IVM), an antiparasitic drug, has a positive effect against Anisakis simplex s.s. infection and has been used for the treatment and prevention of anisakiasis in humans. However, the molecular mechanism of action of IVM on A. simplex s.s. remains unknown. Herein, tandem mass tag (TMT) labeling and extensive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis were used to identify the effect of IVM on the proteome of A. simplex s.s. in vitro. During the study, 3433 proteins, of which 1247 had at least two protein unique peptides, were identified. Comparative proteomics analysis revealed that 59 proteins were differentially regulated (DRPs) in IVM-treated larvae, of which 14 proteins were upregulated and 38 were downregulated after 12 h of culture, but after 24 h, 12 proteins were upregulated and 22 were downregulated. The transcription level of five randomly selected DRPs was determined by real-time PCR as a supplement to the proteomic data. The functional enrichment analysis showed that most of the DRPs were involved in oxidoreductase activity, immunogenicity, protein degradation, and other biological processes. This study has, for the first time, provided comprehensive proteomics data on A. simplex s.s. response to IVM and might deliver new insight into the molecular mechanism by which IVM acts on invasive larvae of A. simplex s.s.


Subject(s)
Anisakiasis/genetics , Anisakis/drug effects , Ivermectin/pharmacology , Proteome/genetics , Animals , Anisakiasis/drug therapy , Anisakiasis/parasitology , Anisakis/pathogenicity , Chromatography, Liquid , Gene Expression Regulation/drug effects , Humans , Larva/drug effects , Larva/pathogenicity , Proteomics , Tandem Mass Spectrometry
4.
Bull Exp Biol Med ; 170(5): 649-653, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1159147

ABSTRACT

Ivermectin (IVM) belongs to the class of macrocyclic lactones, which is used as an antiparasitic agent. At present, the researchers focus on possibility to use IVM in treatment of certain forms of cancer and viral diseases such as COVID-19. The mechanisms of IVM action are not clear. It is assumed that IVM affects chloride channels and increases cytoplasmic concentration of chloride. This study examines the effect of IVM on chloride currents induced by glycine (IGly). Experiments were carried out on isolated pyramidal neurons of the rat hippocampus with whole-cell patch clamp. A short-term (600 msec) application of IVM in a concentration of 10 µM induced a slow inward current, which persisted after washing the neurons. The low concentrations (0.1-1000 nM) of IVM did not induce any novel current, but it rapidly and reversibly reduced the peak amplitude and accelerated desensitization of IGly in a dose-dependent manner. The threshold concentrations of IVM sufficient to reduce peak amplitude of IGly and to accelerate desensitization of IGly were 100 nM and 0.1 nM, respectively. The study revealed a high sensitivity of neuronal glycine receptors to IVM.


Subject(s)
Chloride Channels/drug effects , Glycine/pharmacology , Ivermectin/pharmacology , Pyramidal Cells/drug effects , Action Potentials/drug effects , Animals , Antiviral Agents/pharmacology , Cells, Cultured , Chloride Channels/metabolism , Dose-Response Relationship, Drug , Hippocampus/cytology , Hippocampus/metabolism , Ion Channel Gating/drug effects , Patch-Clamp Techniques , Pyramidal Cells/physiology , Rats , Rats, Wistar , Receptors, Glycine/drug effects , Receptors, Glycine/metabolism
5.
EPMA J ; 11(2): 289-309, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-1086691

ABSTRACT

Relevance: Ivermectin, as an old anti-parasite drug, can suppress almost completely the growth of various human cancers, including ovarian cancer (OC). However, its anticancer mechanism remained to be further studied at the molecular levels. Ivermectin-related molecule-panel changes will serve a useful tool for its personalized drug therapy and prognostic assessment in OCs. Purpose: To explore the functional significance of ivermectin-mediated lncRNA-EIF4A3-mRNA axes in OCs and ivermectin-related molecule-panel for its personalized drug therapy monitoring. Methods: Based on our previous study, a total of 16 lncRNA expression patterns were analyzed using qRT-PCR before and after ivermectin-treated different OC cell lines (TOV-21G and A2780). Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics was used to analyze the protein expressions of EIF4A3 and EIF4A3-binding mRNAs in ovarian cancer cells treated with and without ivermectin. A total of 411 OC patients from the Cancer Genome Atlas (TCGA) database with the selected lncRNA expressions and the corresponding clinical data were included. Lasso regression was constructed to examine the relationship between lncRNA signature and OC survival risk. The overall survival analysis between high-risk and low-risk groups used the Kaplan-Meier method. Heatmap showed the correlation between risk groups and clinical characteristics. The univariate and multivariate models were established with Cox regression. Results: SILAC-based quantitative proteomics found the protein expression levels of EIF4A3 and 116 EIF4A3-binding mRNAs were inhibited by ivermectin in OC cells. Among the analyzed 16 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, LINC00565, SNHG3, PLCH1-AS1, WWTR1-AS1, LINC00517, AL109767.1, STARD13-IT1, LBX2-AS1, LEMD1-AS1, and HOXC-AS3), only 7 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, and LINC00565) were obtained for further lasso regression when combined with the results of drug testing and overall survival analysis. Lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565). The high-risk and low-risk groups based on the prognostic model were significantly related to overall survival and clinicopathologic characteristics (survival status, lymphatic invasion, cancer status, and clinical stage) in OC patients and remained independent risk factors according to multivariate COX analysis (p < 0.05). Conclusion: Those findings provided the potential targeted lncRNA-EIF4A3-mRNA pathways of ivermectin in OC, and constructed the effective prognostic model, which benefits discovery of novel mechanism of ivermectin to suppress ovarian cancer cells, and the ivermectin-related molecule-panel changes benefit for its personalized drug therapy and prognostic assessment towards its predictive, preventive, and personalized medicine (PPPM) in OCs.

6.
J Biomol Struct Dyn ; : 1-14, 2020 Nov 02.
Article in English | MEDLINE | ID: covidwho-1026871

ABSTRACT

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPß1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing -5.30 kcal/mol and -84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting -6.9 kcal/mol and -66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs.

7.
Trends Parasitol ; 37(1): 48-64, 2021 01.
Article in English | MEDLINE | ID: covidwho-943553

ABSTRACT

Here we tell the story of ivermectin, describing its anthelmintic and insecticidal actions and recent studies that have sought to reposition ivermectin for the treatment of other diseases that are not caused by helminth and insect parasites. The standard theory of its anthelmintic and insecticidal mode of action is that it is a selective positive allosteric modulator of glutamate-gated chloride channels found in nematodes and insects. At higher concentrations, ivermectin also acts as an allosteric modulator of ion channels found in host central nervous systems. In addition, in tissue culture, at concentrations higher than anthelmintic concentrations, ivermectin shows antiviral, antimalarial, antimetabolic, and anticancer effects. Caution is required before extrapolating from these preliminary repositioning experiments to clinical use, particularly for Covid-19 treatment, because of the high concentrations of ivermectin used in tissue-culture experiments.


Subject(s)
Anthelmintics/pharmacology , Insecticides/pharmacology , Ivermectin/pharmacology , Animals , Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cell Line , Chloride Channels/drug effects , Dengue Virus/drug effects , Ion Channels/drug effects , Nematoda/drug effects , SARS-CoV-2/drug effects
8.
Med Hypotheses ; 146: 110364, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-909135

ABSTRACT

In an effort to curb the global pandemic due to coronavirus, the scientific community is exploring various treatment strategies with a special emphasis on drug repurposing. Ivermectin, an anti-helminthic drug is also being proposed for treatment and prevention of COVID-19. Ivermectin has demonstrated broad spectrum antiviral activity against both DNA and RNA viruses. Due to its potential to interfere with transport of SARS-CoV-2 nucleocapsid protein to nucleus, it is being proposed to have antiviral activity against this virus as well which has been confirmed in an in-vitro study. However, in-vitro to in-vivo extrapolation studies indicate an inability to achieve the desired IC50 levels of ivermectin after oral administration of doses up to 10 times higher than the approved anti-helminthic dose. In a modelling simulation study, drug accumulation in the lungs was noticed at levels having potential antiviral activity. It is hypothesised that inhaled formulation of ivermectin may be effective against SARS-CoV-2. Therefore, ivermectin administered via inhalational route needs to be explored for potential beneficial role in COVID-19 in preclinical and clinical studies. We also hypothesise the possibility of drug having anti-inflammatory action in coronavirus associated severe respiratory illness based on few in-vitro and in-vivo reports which however needs to be confirmed clinically.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , COVID-19/drug therapy , Drug Repositioning , Ivermectin/administration & dosage , Models, Biological , Pandemics , SARS-CoV-2 , Administration, Inhalation , Anthelmintics/administration & dosage , Anthelmintics/pharmacokinetics , Anti-Inflammatory Agents/pharmacokinetics , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , COVID-19/metabolism , Computer Simulation , Humans , Ivermectin/pharmacokinetics , Lung/metabolism
9.
J Cell Physiol ; 236(4): 2959-2975, 2021 04.
Article in English | MEDLINE | ID: covidwho-777472

ABSTRACT

Viruses such as human cytomegalovirus (HCMV), human papillomavirus (HPV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) represent a great burden to human health worldwide. FDA-approved anti-parasite drug ivermectin is also an antibacterial, antiviral, and anticancer agent, which offers more potentiality to improve global public health, and it can effectively inhibit the replication of SARS-CoV-2 in vitro. This study sought to identify ivermectin-related virus infection pathway alterations in human ovarian cancer cells. Stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomics was used to analyze human ovarian cancer cells TOV-21G treated with and without ivermectin (20 µmol/L) for 24 h, which identified 4447 ivermectin-related proteins in ovarian cancer cells. Pathway network analysis revealed four statistically significant antiviral pathways, including HCMV, HPV, EBV, and HIV1 infection pathways. Interestingly, compared with the reported 284 SARS-CoV-2/COVID-19-related genes from GencLip3, we identified 52 SARS-CoV-2/COVID-19-related protein alterations when treated with and without ivermectin. Protein-protein network (PPI) was constructed based on the interactions between 284 SARS-CoV-2/COVID-19-related genes and between 52 SARS-CoV-2/COVID-19-related proteins regulated by ivermectin. Molecular complex detection analysis of PPI network identified three hub modules, including cytokines and growth factor family, MAP kinase and G-protein family, and HLA class proteins. Gene Ontology analysis revealed 10 statistically significant cellular components, 13 molecular functions, and 11 biological processes. These findings demonstrate the broad-spectrum antiviral property of ivermectin benefiting for COVID-19 treatment in the context of predictive, preventive, and personalized medicine in virus-related diseases.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Ivermectin/pharmacology , Cell Line, Tumor , Humans , Proteomics/methods , SARS-CoV-2
10.
In Vivo ; 34(5): 3023-3026, 2020.
Article in English | MEDLINE | ID: covidwho-740631

ABSTRACT

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One drug that has attracted interest is the antiparasitic compound ivermectin, a macrocyclic lactone derived from the bacterium Streptomyces avermitilis. We carried out a docking study to determine if ivermectin might be able to attach to the SARS-CoV-2 spike receptor-binding domain bound with ACE2. MATERIALS AND METHODS: We used the program AutoDock Vina Extended to perform the docking study. RESULTS: Ivermectin docked in the region of leucine 91 of the spike and histidine 378 of the ACE2 receptor. The binding energy of ivermectin to the spike-ACE2 complex was -18 kcal/mol and binding constant was 5.8 e-08. CONCLUSION: The ivermectin docking we identified may interfere with the attachment of the spike to the human cell membrane. Clinical trials now underway should determine whether ivermectin is an effective treatment for SARS-Cov2 infection.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Ivermectin/chemistry , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , Betacoronavirus/chemistry , Betacoronavirus/pathogenicity , Binding Sites/drug effects , COVID-19 , Cell Membrane/drug effects , Coronavirus Infections/virology , Drug Repositioning , Histidine/chemistry , Humans , Ivermectin/therapeutic use , Leucine/chemistry , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral/virology , SARS-CoV-2 , Streptomyces/chemistry
11.
Antiviral Res ; 178: 104787, 2020 06.
Article in English | MEDLINE | ID: covidwho-30819

ABSTRACT

Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ~5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/virology , Drug Approval , Ivermectin/pharmacology , Ivermectin/therapeutic use , Pneumonia, Viral/virology , Virus Replication/drug effects , Animals , Australia , Betacoronavirus/physiology , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Humans , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Vero Cells
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