Analgesics
Antiandrogens
Azvudine
Bromhexine
Budesonide
Colchicine
Conv. Plasma
Curcumin
Famotidine
Favipiravir
Fluvoxamine
Hydroxychlor..
Ivermectin
Lifestyle
Melatonin
Metformin
Minerals
Molnupiravir
Monoclonals
Naso/orophar..
Nigella Sativa
Nitazoxanide
Paxlovid
Quercetin
Remdesivir
Thermotherapy
Vitamins
More

Other
Feedback
Home
Top
Abstract
All lactoferrin studies
Meta analysis
 
Feedback
Home
next
study
previous
study
c19early.org COVID-19 treatment researchLactoferrinLactoferrin (more..)
Melatonin Meta
Metformin Meta
Azvudine Meta
Bromhexine Meta Molnupiravir Meta
Budesonide Meta
Colchicine Meta
Conv. Plasma Meta Nigella Sativa Meta
Curcumin Meta Nitazoxanide Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

All Studies   Meta Analysis    Recent:   

Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells

Ostrov et al., Pathogens, doi:10.3390/pathogens10111514
Nov 2021  
  Post
  Facebook
Share
  Source   PDF   All Studies   Meta AnalysisMeta
Vero E6 and H23 In Vitro study finding SARS-CoV-2 antiviral activity associated with agonism of the sigma-1 receptor, ligation of the sigma-2 receptor, and a combination of the two. Authors identify synergistic effects with the combination of diphenhydramine and lactoferrin.
Ostrov et al., 20 Nov 2021, peer-reviewed, 16 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperLactoferrinAll
Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells
David A Ostrov, Andrew P Bluhm, Danmeng Li, Juveriya Qamar Khan, Megha Rohamare, Karthic Rajamanickam, Kalpana K. Bhanumathy, Jocelyne Lew, Darryl Falzarano, Franco J Vizeacoumar, Joyce A Wilson, Marco Mottinelli, Siva Rama Raju Kanumuri, Abhisheak Sharma, Christopher R Mccurdy, Michael H Norris
Pathogens, doi:10.3390/pathogens10111514
1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). ( 3 ) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.
Controls included total LDH release as measured by lysis of all cells, spontaneous release from uninfected cells, and media alone. The toxicity of sigma ligands alone were also determined in parallel to discriminate the amount of SARS-CoV-2-induced cytotoxicity occurring in the presence of a given treatment. After spontaneous and background subtraction, OD 450 values were transformed to a percent of SARS-CoV-2 infected cells (100%) in the absence of any drug treatment to obtain percent of SARS-CoV-2-induced cytotoxicity. These experiments were carried out twice. Plaque Reduction Assay Vero E6 cells were plated in 24-well plates with triplicate replicates on different plates. Virus master mix was used to dilute down to 20-200 PFU/mL and aliquoted in separate tubes with drugs at the final indicated drug concentrations. The drug virus mixtures were immediately used to infect Vero E6 monolayers for 1 h with rocking every 10 min. Monolayers were then overlaid with MEM in 1.5% low-melt agarose containing drugs at the final concentrations indicated. Plaques were counted at 72 hours post infection and used to calculate the apparent reduction in viral concentration compared to the starting volume. Data presented is representative of two independent experiments. Generation of ACE-2 Lentivirus Particles The lentivirus containing ACE2 were generated by co-transfecting psPAX2, pMD2.G, and an ACE expression vector that also contained a blasticidin selection gene EX-U1285-Lv197..
References
Abate, Niso, Berardi, Sigma-2 receptor: Past, present and perspectives on multiple therapeutic exploitations, Futur. Med. Chem, doi:10.4155/fmc-2018-0072
Arnold, Bordoli, Kopp, Schwede, The SWISS-MODEL workspace: A web-based environment for protein structure homology modelling, Bioinformatics, doi:10.1093/bioinformatics/bti770
Basile, Paul, Mirchevich, Kuijpers, De Costa, Modulation of (+)-[3H]pentazocine binding to guinea pig cerebellum by divalent cations, Mol. Pharmacol
Cirino, Eans, Medina, Wilson, Mottinelli et al., Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain, Front. Pharmacol, doi:10.3389/fphar.2019.00678
Cunningham, Li, Vizeacoumar, Bhanumathy, Lee et al., Therapeutic relevance of the protein phosphatase 2A in cancer, Oncotarget, doi:10.18632/oncotarget.11399
Fung, Huang, Liu, Coronavirus-induced ER stress response and its involvement in regulation of coronavirus-host interactions, Virus Res, doi:10.1016/j.virusres.2014.09.016
Fung, Liu, Coronavirus infection, ER stress, apoptosis and innate immunity, Front. Microbiol, doi:10.3389/fmicb.2014.00296
Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature, doi:10.1038/s41586-020-2286-9
Hayashi, The Sigma-1 Receptor in Cellular Stress Signaling, Front. Neurosci, doi:10.3389/fnins.2019.00733
Hernández, Gabrielli, Costa, Uttaro, Phagocytic and pinocytic uptake of cholesterol in Tetrahymena thermophila impact differently on gene regulation for sterol homeostasis, Sci. Rep, doi:10.1038/s41598-021-88737-z
Hu, Meng, Zhang, Xiang, Wang, The in vitro antiviral activity of lactoferrin against common human coronaviruses and SARS-CoV-2 is mediated by targeting the heparan sulfate co-receptor, Emerg. Microbes Infect, doi:10.1080/22221751.2021.1888660
Intagliata, Sharma, King, Mesangeau, Seminerio et al., Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo, AAPS J, doi:10.1208/s12248-020-00472-x
Jamalapuram, Vuppala, Abdelazeem, Mccurdy, Avery, Ultra-performance liquid chromatography tandem mass spectrometry method for the determination of AZ66, a sigma receptor ligand, in rat plasma and its application to in vivo pharmacokinetics, Biomed. Chromatogr, doi:10.1002/bmc.2901
James, Shen, Zavaleta, Nielsen, Mesangeau et al., New Positron Emission Tomography (PET) Radioligand for Imaging σ-1 Receptors in Living Subjects, J. Med. Chem, doi:10.1021/jm300371c
Jang, Jeon, Kim, Lee, Drugs repurposed for COVID-19 by virtual screening of 6218 drugs and cell-based assay, Proc. Natl. Acad. Sci, doi:10.1073/pnas.2024302118
Jeon, Ko, Lee, Choi, Byun et al., Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs, Antimicrob. Agents Chemother, doi:10.1128/AAC.00819-20
Joshi, Joshi, Degani, Tackling SARS-CoV-2: Proposed targets and repurposed drugs, Futur. Med. Chem, doi:10.4155/fmc-2020-0147
Kawamura, Ishiwata, Tajima, Ishii, Matsuno et al., In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors, Nucl. Med. Biol, doi:10.1016/S0969-8051(00)00081-0
Kulemina, Ostrov, Prediction of Off-Target Effects on Angiotensin-Converting Enzyme 2, J. Biomol. Screen, doi:10.1177/1087057111413919
Lane, Ekins, Defending Antiviral Cationic Amphiphilic Drugs That May Cause Drug-Induced Phospholipidosis, J. Chem. Inf. Model, doi:10.1021/acs.jcim.1c00903
Li, Han, Dai, Xu, He et al., Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide, Nat. Commun, doi:10.1038/s41467-021-21171-x
Li, Zhang, Yao, Xiang, Ma et al., Sigma-1 receptor agonist increases axon outgrowth of hippocampal neurons via voltage-gated calcium ions channels, CNS Neurosci. Ther, doi:10.1111/cns.12768
Long, Hassan, Thompson, Mcdonald, Wang et al., Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition, Nat. Commun, doi:10.1038/s41467-019-10279-w
Matsuno, Nakazawa, Okamoto, Kawashima, Mita, Binding properties of SA4503, a novel and selective sigma 1 receptor agonist, Eur J. Pharmacol, doi:10.1016/0014-2999(96)00201-4
Mirabelli, Wotring, Zhang, Mccarty, Fursmidt et al., Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19, bioRxiv, doi:10.1073/pnas.2105815118
Morris, Huey, Lindstrom, Sanner, Belew et al., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, J. Comput. Chem, doi:10.1002/jcc.21256
Mésangeau, Narayanan, Green, Shaikh, Kaushal et al., Conversion of a Highly Selective Sigma-1 Receptor-Ligand to Sigma-2 Receptor Preferring Ligands with Anticocaine Activity, J. Med. Chem, doi:10.1021/jm701357m
Poduri, Joshi, Jagadeesh, Drugs targeting various stages of the SARS-CoV-2 life cycle: Exploring promising drugs for the treatment of covid-19, Cell Signal, doi:10.1016/j.cellsig.2020.109721
Reznikov, Norris, Vashisht, Bluhm, Li et al., Identification of antiviral antihistamines for COVID-19 repurposing, Biochem. Biophys. Res. Commun, doi:10.1016/j.bbrc.2020.11.095
Riva, Yuan, Yin, Martin-Sancho, Matsunaga et al., Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing, Nature
Seminerio, Robson, Abdelazeem, Mesangeau, Jamalapuram et al., Synthesis and Pharmacological Characterization of a Novel Sigma Receptor Ligand with Improved Metabolic Stability and Antagonistic Effects Against Methamphetamine, AAPS J, doi:10.1208/s12248-011-9311-8
Shi, Shuai, Wen, Wang, Yan et al., The preclinical inhibitor GS441524 in combination with GC376 efficaciously inhibited the proliferation of SARS-CoV-2 in the mouse respiratory tract, Emerg. Microbes Infect, doi:10.1080/22221751.2021.1899770
Sola, Almazán, Zúñiga, Enjuanes, Continuous and Discontinuous RNA Synthesis in Coronaviruses, Annu. Rev. Virol, doi:10.1146/annurev-virology-100114-055218
Tummino, Rezelj, Fischer, Fischer, O'meara et al., Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2, Science, doi:10.1126/science.abi4708
Vela, Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?, Front. Pharmacol, doi:10.3389/fphar.2020.582310
Xiu, Dick, Ju, Mirzaie, Abdi et al., Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities, J. Med. Chem, doi:10.1021/acs.jmedchem.0c00502
Xu, Kaushal, Shaikh, Wilson, Mésangeau et al., A Novel Substituted Piperazine, CM156, Attenuates the Stimulant and Toxic Effects of Cocaine in Mice, J. Pharmacol. Exp. Ther, doi:10.1124/jpet.109.161398
Yang, Zeng, Wang, Sun, Yin et al., Sigma-2 Receptor-A Potential Target for Cancer/Alzheimer's Disease Treatment via Its Regulation of Cholesterol Homeostasis, Molecules, doi:10.3390/molecules25225439
Zeng, Riad, Mach, The Biological Function of Sigma-2 Receptor/TMEM97 and Its Utility in PET Imaging Studies in Cancer, Cancers, doi:10.3390/cancers12071877
Zheng, Ma, Xiong, Fan, Efficacy and safety of direct acting antiviral regimens for hepatitis C virus and human immunodeficiency virus co-infection: Systematic review and network meta-analysis, J. Gastroenterol. Hepatol
Zhou, Hou, Shen, Huang, Martin et al., Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2, Cell Discov, doi:10.1038/s41421-020-0153-3
Loading..
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop   
Submit