Dimethoxycurcumin Acidifies Endolysosomes and Inhibits SARS-CoV-2 Entry
Nabab Khan, Zahra Afghah, Aparajita Baral, Jonathan D Geiger, Xuesong Chen
Frontiers in Virology, doi:10.3389/fviro.2022.923018
The pandemic of coronavirus disease 2019 caused by infection by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) continues to take a huge toll on global health. Although improving, currently there are only limited therapies against SARS-CoV-2. Curcumin, a natural polyphenol, exerts antiviral effects against a wide variety of viruses and can inhibit SARS-CoV-2 entry. However, undesirable physicochemical and pharmacokinetic properties of curcumin limit its clinical application. Here, we determined the effects of dimethoxycurcumin (DiMC), a methylated analog of curcumin with improved bioavailability, on the entry of SARS-CoV-2. DiMC blocked entry of pseudo-SARS-CoV-2 into Calu-3 human non-small cell lung adenocarcinoma cells and Vero E6 green monkey kidney epithelial cells. Mechanistically, DiMC acidified lysosomes, enhanced lysosome degradation capabilities, and promoted lysosome degradation of angiotensin converting enzyme 2 (ACE2), a major receptor for SARS-CoV-2 entry, as well as pseudo-SARS-CoV-2 and the SARS-CoV-2 S1 protein. Furthermore, other lysosome acidifying agents, including the TRPML1 agonist ML-SA1 and the BK channel activator NS1619, also blocked the entry of pseudo-SARS-CoV-2. Thus, the anti-SARS-CoV-2 potential of DiMC and lysosome acidifying agents might be explored further as possible effective therapeutic strategies against COVID-19.
AUTHOR CONTRIBUTIONS NK and XC designed the research. NK performed all the experiments, analyzed the data, and drafted the manuscript. ZA analyzed data. AB performed immunoblotting. XC and JG wrote the manuscript.
Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Abella, Jolkovsky, Biney, Uspal, Hyman et al., and Safety of Hydroxychloroquine vs Placebo for Pre-Exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial, JAMA Intern Med,
doi:10.1001/jamainternmed.2020.6319Anderson, Vanslyke, Thulin, Jean, Thomas, Activation of the Furin Endoprotease Is a Multiple-Step Process: Requirements for Acidification and Internal Propeptide Cleavage, EMBO J,
doi:10.1093/emboj/16.7.1508Arabi, Gordon, Derde, Nichol, Murthy et al., Lopinavir-Ritonavir and Hydroxychloroquine for Critically Ill Patients With COVID-19: REMAP-CAP Randomized Controlled Trial, Intensive Care Med,
doi:10.1007/s00134-021-06448-5Barnabas, Brown, Bershteyn, Karita, Johnston et al., Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial, Ann Intern Med,
doi:10.7326/M20-6519Bayati, Kumar, Francis, Mcpherson, SARS-CoV-2 Infects Cells After Viral Entry via Clathrin-Mediated Endocytosis, J Biol Chem,
doi:10.1016/j.jbc.2021.100306Boechat, Chora, Morais, Delgado, The Immune Response to SARS-CoV-2 and COVID-19 Immunopathology -Current Perspectives, Pulmonology,
doi:10.1016/j.pulmoe.2021.03.008Chia, Gasnereau, Lieu, Gleeson, Rab9-Dependent Retrograde Transport and Endosomal Sorting of the Endopeptidase Furin, J Cell Sci,
doi:10.1242/jcs.083782Datta, Miller, Halcrow, Khan, Colwell et al., SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy, Front Cell Neurosci,
doi:10.3389/fncel.2021.777738Ghosh, Dellibovi-Ragheb, Kerviel, Pak, Qiu et al., Beta-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway, Cell,
doi:10.1016/j.cell.2020.10.039Goc, Sumera, Rath, Niedzwiecki, Phenolic Compounds Disrupt Spike-Mediated Receptor-Binding and Entry of SARS-CoV-2 Pseudo-Virions, PloS One,
doi:10.1371/journal.pone.0253489Hamming, Timens, Bulthuis, Lely, Navis et al., Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis, J Pathol,
doi:10.1002/path.1570Hoffmann, Kleine-Weber, Pohlmann, A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells, Mol Cell,
doi:10.1016/j.molcel.2020.04.022Hoffmann, Kleine-Weber, Schroeder, Kruger, Herrler et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Hoffmann, Mosbauer, Hofmann-Winkler, Kaul, Kleine-Weber et al., Chloroquine Does Not Inhibit Infection of Human Lung Cells With SARS-CoV-2, Nature,
doi:10.1038/s41586-020-2575-3Jena, Kanungo, Nayak, Chainy, Dandapat, Catechin and Curcumin Interact With S Protein of SARS-CoV2 and ACE2 of Human Cell Membrane: Insights From Computational Studies, Sci Rep,
doi:10.1038/s41598-021-81462-7Khan, Lakpa, Halcrow, Afghah, Miller et al., BK Channels Regulate Extracellular Tat-Mediated HIV-1 LTR Transactivation, Sci Rep,
doi:10.1038/s41598-019-48777-yKoch, Uckeley, Doldan, Stanifer, Boulant et al., TMPRSS2 Expression Dictates the Entry Route Used by SARS-CoV-2 to Infect Host Cells, EMBO J,
doi:10.15252/embj.2021107821Leon, Michelson, Olejnik, Chowdhary, Oh et al., A Virus-Specific Monocyte Inflammatory Phenotype is Induced by SARS-CoV-2 at the Immune-Epithelial Interface, Proc Natl Acad Sci,
doi:10.1073/pnas.2116853118Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a Less Toxic Derivative of Chloroquine, is Effective in Inhibiting SARS-CoV-2 Infection In Vitro, Cell Discovery,
doi:10.1038/s41421-020-0156-0Mcguire, Stransky, Cotter, Forgac, Regulation of V-ATPase Activity, Front Biosci,
doi:10.2741/4506Mitja, Corbacho-Monne, Ubals, Alemany, Suner et al., A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2021801Moustapha, Peretout, Rainey, Sureau, Geze et al., Curcumin Induces Crosstalk Between Autophagy and Apoptosis Mediated by Calcium Release From the Endoplasmic Reticulum, Lysosomal Destabilization and Mitochondrial Events, Cell Death Discovery,
doi:10.1038/cddiscovery.2015.17Ohkuma, Poole, Cytoplasmic Vacuolation of Mouse Peritoneal Macrophages and the Uptake Into Lysosomes of Weakly Basic Substances, J Cell Biol,
doi:10.1083/jcb.90.3.656Ou, Liu, Lei, Li, Mi et al., Characterization of Spike Glycoprotein of SARS-CoV-2 on Virus Entry and its Immune Cross-Reactivity With SARS-CoV, Nat Commun,
doi:10.1038/s41467-020-15562-9Pae, Jeong, Kim, Kim, Song et al., Dimethoxycurcumin, A Synthetic Curcumin Analogue With Higher Metabolic Stability, Inhibits NO Production, Inducible NO Synthase Expression and NF-kappaB Activation in RAW264.7 Macrophages Activated With LPS, Mol Nutr Food Res,
doi:10.1002/mnfr.200700333Patel, Rajendran, Shah, Patel, Pakala et al., Virtual Screening of Curcumin and its Analogs Against the Spike Surface Glycoprotein of SARS-CoV-2 and SARS-CoV, J Biomol Struct Dyn,
doi:10.1080/07391102.2020.1868338Patwardhan, Checker, Sharma, Kohli, Priyadarsini et al., Dimethoxycurcumin, a Metabolically Stable Analogue of Curcumin, Exhibits Anti-Inflammatory Activities in Murine and Human Lymphocytes, Biochem Pharmacol,
doi:10.1016/j.bcp.2011.06.024Schaefer, Jung, Hummer, Binding of SARS-CoV-2 Fusion Peptide to Host Endosome and Plasma Membrane, J Phys Chem B,
doi:10.1021/acs.jpcb.1c04176Sharifi-Rad, Rayess, Rizk, Sadaka, Zgheib et al., Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications, Front Pharmacol,
doi:10.3389/fphar.2020.01021Shereen, Khan, Kazmi, Bashir, Siddique, COVID-19 Infection: Origin, Transmission, and Characteristics of Human Coronaviruses, J Adv Res,
doi:10.1016/j.jare.2020.03.005Simon, Aswini, Kumar, Mankadath, Curcumin and Its Synthetic Analogue Dimethoxycurcumin Differentially Modulates Antioxidant Status of Normal Human Peripheral Blood Mononuclear Cells, Free Radic Res,
doi:10.1080/10715762.2018.1455002Sivapalan, Ulrik, Lapperre, Bojesen, Eklof et al., Azithromycin and Hydroxychloroquine in Hospitalised Patients With Confirmed COVID-19: A Randomised Double-Blinded Placebo-Controlled Trial, Eur Respir J,
doi:10.1183/13993003.00752-2021Sohail, Guo, Yang, Li, Li et al., A Promising Anticancer Agent Dimethoxycurcumin: Aspects of Pharmacokinetics, Efficacy, Mechanism, and Nanoformulation for Drug Delivery, Front Pharmacol,
doi:10.3389/fphar.2021.665387Song, Malampati, Zeng, Durairajan, Yang et al., A Small Molecule Transcription Factor EB Activator Ameliorates Beta-Amyloid Precursor Protein and Tau Pathology in Alzheimer's Disease Models, Aging Cell,
doi:10.1111/acel.13069Song, Sun, Peluso, Zeng, Yu et al., A Novel Curcumin Analog Binds to and Activates TFEB In Vitro and In Vivo Independent of MTOR Inhibition, Autophagy,
doi:10.1080/15548627.2016.1179404Tamvakopoulos, Dimas, Sofianos, Hatziantoniou, Han et al., Metabolism and Anticancer Activity of the Curcumin Analogue, Dimethoxycurcumin, Clin Cancer Res,
doi:10.1158/1078-0432.CCR-06-1839Tang, Bidon, Jaimes, Whittaker, Daniel, Coronavirus Membrane Fusion Mechanism Offers a Potential Target for Antiviral Development, Antiviral Res,
doi:10.1016/j.antiviral.2020.104792Teymouri, Barati, Pirro, Sahebkar, Biological and Pharmacological Evaluation of Dimethoxycurcumin: A Metabolically Stable Curcumin Analogue With a Promising Therapeutic Potential, J Cell Physiol,
doi:10.1002/jcp.25749Walls, Xiong, Park, Tortorici, Snijder et al., Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion, Cell,
doi:10.1016/j.cell.2018.12.028Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus 2019-Ncov) In Vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Wrapp, Wang, Corbett, Goldsmith, Hsieh et al., Cryo-EM Structure of the 2019-Ncov Spike in the Prefusion Conformation, Science,
doi:10.1126/science.abb2507Xia, Zhu, Liu, Lan, Xu et al., Fusion Mechanism of 2019-Ncov and Fusion Inhibitors Targeting HR1 Domain in Spike Protein, Cell Mol Immunol,
doi:10.1038/s41423-020-0374-2Yao, Ye, Zhang, Cui, Huang et al., In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clin Infect Dis,
doi:10.1093/cid/ciaa237Yoon, Kang, Lee, Kim, Kim et al., Stronger Proteasomal Inhibition and Higher CHOP Induction are Responsible for More Effective Induction of Paraptosis by Dimethoxycurcumin Than Curcumin, Cell Death Dis,
doi:10.1038/cddis.2014.85Zhang, Wang, Xu, Lu, Jiang et al., Curcumin Targets the TFEB-Lysosome Pathway for Induction of Autophagy, Oncotarget,
doi:10.18632/oncotarget.12318DOI record:
{
"DOI": "10.3389/fviro.2022.923018",
"ISSN": [
"2673-818X"
],
"URL": "http://dx.doi.org/10.3389/fviro.2022.923018",
"abstract": "<jats:p>The pandemic of coronavirus disease 2019 (COVID-19) caused by infection by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) continues to take a huge toll on global health. Although improving, currently there are only limited therapies against SARS-CoV-2. Curcumin, a natural polyphenol, exerts antiviral effects against a wide variety of viruses and can inhibit SARS-CoV-2 entry. However, undesirable physicochemical and pharmacokinetic properties of curcumin limit its clinical application. Here, we determined the effects of dimethoxycurcumin (DiMC), a methylated analog of curcumin with improved bioavailability, on the entry of SARS-CoV-2. DiMC blocked entry of pseudo-SARS-CoV-2 into Calu-3 human non-small cell lung adenocarcinoma cells and Vero E6 green monkey kidney epithelial cells. Mechanistically, DiMC acidified lysosomes, enhanced lysosome degradation capabilities, and promoted lysosome degradation of angiotensin converting enzyme 2 (ACE2), a major receptor for SARS-CoV-2 entry, as well as pseudo-SARS-CoV-2 and the SARS-CoV-2 S1 protein. Furthermore, other lysosome acidifying agents, including the TRPML1 agonist ML-SA1 and the BK channel activator NS1619, also blocked the entry of pseudo-SARS-CoV-2. Thus, the anti-SARS-CoV-2 potential of DiMC and lysosome acidifying agents might be explored further as possible effective therapeutic strategies against COVID-19.</jats:p>",
"alternative-id": [
"10.3389/fviro.2022.923018"
],
"author": [
{
"affiliation": [],
"family": "Khan",
"given": "Nabab",
"sequence": "first"
},
{
"affiliation": [],
"family": "Afghah",
"given": "Zahra",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Baral",
"given": "Aparajita",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Geiger",
"given": "Jonathan D.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Chen",
"given": "Xuesong",
"sequence": "additional"
}
],
"container-title": "Frontiers in Virology",
"container-title-short": "Front. Virol.",
"content-domain": {
"crossmark-restriction": true,
"domain": [
"frontiersin.org"
]
},
"created": {
"date-parts": [
[
2022,
6,
30
]
],
"date-time": "2022-06-30T09:21:52Z",
"timestamp": 1656580912000
},
"deposited": {
"date-parts": [
[
2022,
6,
30
]
],
"date-time": "2022-06-30T09:21:56Z",
"timestamp": 1656580916000
},
"funder": [
{
"DOI": "10.13039/100000057",
"award": [
"P30GM100329, U54GM115458"
],
"doi-asserted-by": "publisher",
"id": [
{
"asserted-by": "publisher",
"id": "10.13039/100000057",
"id-type": "DOI"
}
],
"name": "National Institute of General Medical Sciences"
},
{
"DOI": "10.13039/100000025",
"award": [
"R01MH100972, R01MH105329, R01MH119000"
],
"doi-asserted-by": "publisher",
"id": [
{
"asserted-by": "publisher",
"id": "10.13039/100000025",
"id-type": "DOI"
}
],
"name": "National Institute of Mental Health"
},
{
"DOI": "10.13039/100000065",
"award": [
"2R01NS065957"
],
"doi-asserted-by": "publisher",
"id": [
{
"asserted-by": "publisher",
"id": "10.13039/100000065",
"id-type": "DOI"
}
],
"name": "National Institute of Neurological Disorders and Stroke"
},
{
"DOI": "10.13039/100000026",
"award": [
"2R01DA032444"
],
"doi-asserted-by": "publisher",
"id": [
{
"asserted-by": "publisher",
"id": "10.13039/100000026",
"id-type": "DOI"
}
],
"name": "National Institute on Drug Abuse"
}
],
"indexed": {
"date-parts": [
[
2024,
9,
15
]
],
"date-time": "2024-09-15T21:55:52Z",
"timestamp": 1726437352299
},
"is-referenced-by-count": 4,
"issued": {
"date-parts": [
[
2022,
6,
30
]
]
},
"license": [
{
"URL": "https://creativecommons.org/licenses/by/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2022,
6,
30
]
],
"date-time": "2022-06-30T00:00:00Z",
"timestamp": 1656547200000
}
}
],
"link": [
{
"URL": "https://www.frontiersin.org/articles/10.3389/fviro.2022.923018/full",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "1965",
"original-title": [],
"prefix": "10.3389",
"published": {
"date-parts": [
[
2022,
6,
30
]
]
},
"published-online": {
"date-parts": [
[
2022,
6,
30
]
]
},
"publisher": "Frontiers Media SA",
"reference": [
{
"DOI": "10.1016/j.jare.2020.03.005",
"article-title": "COVID-19 Infection: Origin, Transmission, and Characteristics of Human Coronaviruses",
"author": "Shereen",
"doi-asserted-by": "publisher",
"journal-title": "J Adv Res",
"key": "B1",
"volume": "24",
"year": "2020"
},
{
"DOI": "10.1016/S0140-6736(20)30185-9",
"article-title": "A Novel Coronavirus Outbreak of Global Health Concern",
"author": "Wang",
"doi-asserted-by": "publisher",
"journal-title": "Lancet",
"key": "B2",
"volume": "395",
"year": "2020"
},
{
"DOI": "10.1038/s41467-020-15562-9",
"article-title": "Characterization of Spike Glycoprotein of SARS-CoV-2 on Virus Entry and its Immune Cross-Reactivity With SARS-CoV",
"author": "Ou",
"doi-asserted-by": "publisher",
"first-page": "1620",
"journal-title": "Nat Commun",
"key": "B3",
"volume": "11",
"year": "2020"
},
{
"DOI": "10.1073/pnas.2003138117",
"article-title": "Cell Entry Mechanisms of SARS-CoV-2",
"author": "Shang",
"doi-asserted-by": "publisher",
"journal-title": "Proc Natl Acad Sci USA",
"key": "B4",
"volume": "117",
"year": "2020"
},
{
"DOI": "10.1016/j.jbc.2021.100306",
"article-title": "SARS-CoV-2 Infects Cells After Viral Entry via Clathrin-Mediated Endocytosis",
"author": "Bayati",
"doi-asserted-by": "publisher",
"first-page": "100306",
"journal-title": "J Biol Chem",
"key": "B5",
"volume": "296",
"year": "2021"
},
{
"DOI": "10.1016/j.tibs.2021.06.001",
"article-title": "Cell Entry by SARS-CoV-2",
"author": "Peng",
"doi-asserted-by": "publisher",
"journal-title": "Trends Biochem Sci",
"key": "B6",
"volume": "46",
"year": "2021"
},
{
"DOI": "10.1038/s41423-020-0374-2",
"article-title": "Fusion Mechanism of 2019-Ncov and Fusion Inhibitors Targeting HR1 Domain in Spike Protein",
"author": "Xia",
"doi-asserted-by": "publisher",
"journal-title": "Cell Mol Immunol",
"key": "B7",
"volume": "17",
"year": "2020"
},
{
"DOI": "10.1021/acs.jpcb.1c04176",
"article-title": "Binding of SARS-CoV-2 Fusion Peptide to Host Endosome and Plasma Membrane",
"author": "Schaefer",
"doi-asserted-by": "publisher",
"journal-title": "J Phys Chem B",
"key": "B8",
"volume": "125",
"year": "2021"
},
{
"DOI": "10.3389/fphar.2021.675287",
"article-title": "Curcumin as a Potential Treatment for COVID-19",
"author": "Rattis",
"doi-asserted-by": "publisher",
"journal-title": "Front Pharmacol",
"key": "B9",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.1038/s41598-021-81462-7",
"article-title": "Catechin and Curcumin Interact With S Protein of SARS-CoV2 and ACE2 of Human Cell Membrane: Insights From Computational Studies",
"author": "Jena",
"doi-asserted-by": "publisher",
"first-page": "2043",
"journal-title": "Sci Rep",
"key": "B10",
"volume": "11",
"year": "2021"
},
{
"DOI": "10.1080/07391102.2020.1868338",
"article-title": "Virtual Screening of Curcumin and its Analogs Against the Spike Surface Glycoprotein of SARS-CoV-2 and SARS-CoV",
"author": "Patel",
"doi-asserted-by": "publisher",
"journal-title": "J Biomol Struct Dyn",
"key": "B11",
"year": "2021"
},
{
"DOI": "10.1371/journal.pone.0253489",
"article-title": "Phenolic Compounds Disrupt Spike-Mediated Receptor-Binding and Entry of SARS-CoV-2 Pseudo-Virions",
"author": "Goc",
"doi-asserted-by": "publisher",
"journal-title": "PloS One",
"key": "B12",
"volume": "16",
"year": "2021"
},
{
"DOI": "10.1002/jcp.25749",
"article-title": "Biological and Pharmacological Evaluation of Dimethoxycurcumin: A Metabolically Stable Curcumin Analogue With a Promising Therapeutic Potential",
"author": "Teymouri",
"doi-asserted-by": "publisher",
"journal-title": "J Cell Physiol",
"key": "B13",
"volume": "233",
"year": "2018"
},
{
"DOI": "10.3389/fphar.2020.01021",
"article-title": "Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications",
"author": "Sharifi-Rad",
"doi-asserted-by": "publisher",
"journal-title": "Front Pharmacol",
"key": "B14",
"volume": "11",
"year": "2020"
},
{
"DOI": "10.3389/fphar.2021.665387",
"article-title": "A Promising Anticancer Agent Dimethoxycurcumin: Aspects of Pharmacokinetics, Efficacy, Mechanism, and Nanoformulation for Drug Delivery",
"author": "Sohail",
"doi-asserted-by": "publisher",
"journal-title": "Front Pharmacol",
"key": "B15",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.1080/10715762.2018.1455002",
"article-title": "Curcumin and Its Synthetic Analogue Dimethoxycurcumin Differentially Modulates Antioxidant Status of Normal Human Peripheral Blood Mononuclear Cells",
"author": "Simon",
"doi-asserted-by": "publisher",
"journal-title": "Free Radic Res",
"key": "B16",
"volume": "52",
"year": "2018"
},
{
"DOI": "10.1016/j.bcp.2011.06.024",
"article-title": "Dimethoxycurcumin, a Metabolically Stable Analogue of Curcumin, Exhibits Anti-Inflammatory Activities in Murine and Human Lymphocytes",
"author": "Patwardhan",
"doi-asserted-by": "publisher",
"journal-title": "Biochem Pharmacol",
"key": "B17",
"volume": "82",
"year": "2011"
},
{
"DOI": "10.1158/1078-0432.CCR-06-1839",
"article-title": "Metabolism and Anticancer Activity of the Curcumin Analogue, Dimethoxycurcumin",
"author": "Tamvakopoulos",
"doi-asserted-by": "publisher",
"journal-title": "Clin Cancer Res",
"key": "B18",
"volume": "13",
"year": "2007"
},
{
"DOI": "10.1038/cddis.2014.85",
"article-title": "Stronger Proteasomal Inhibition and Higher CHOP Induction are Responsible for More Effective Induction of Paraptosis by Dimethoxycurcumin Than Curcumin",
"author": "Yoon",
"doi-asserted-by": "publisher",
"journal-title": "Cell Death Dis",
"key": "B19",
"volume": "5",
"year": "2014"
},
{
"DOI": "10.1016/j.cell.2020.02.052",
"article-title": "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor",
"author": "Hoffmann",
"doi-asserted-by": "publisher",
"first-page": "271",
"journal-title": "Cell",
"key": "B20",
"volume": "181",
"year": "2020"
},
{
"DOI": "10.1038/s41586-020-2575-3",
"article-title": "Chloroquine Does Not Inhibit Infection of Human Lung Cells With SARS-CoV-2",
"author": "Hoffmann",
"doi-asserted-by": "publisher",
"journal-title": "Nature",
"key": "B21",
"volume": "585",
"year": "2020"
},
{
"DOI": "10.1186/s40246-021-00304-9",
"article-title": "ACE2 Nascence, Trafficking, and SARS-CoV-2 Pathogenesis: The Saga Continues",
"author": "Badawi",
"doi-asserted-by": "publisher",
"first-page": "8",
"journal-title": "Hum Genomics",
"key": "B22",
"volume": "15",
"year": "2021"
},
{
"DOI": "10.1038/cddiscovery.2015.17",
"article-title": "Curcumin Induces Crosstalk Between Autophagy and Apoptosis Mediated by Calcium Release From the Endoplasmic Reticulum, Lysosomal Destabilization and Mitochondrial Events",
"author": "Moustapha",
"doi-asserted-by": "publisher",
"first-page": "15017",
"journal-title": "Cell Death Discovery",
"key": "B23",
"volume": "1",
"year": "2015"
},
{
"DOI": "10.18632/oncotarget.12318",
"article-title": "Curcumin Targets the TFEB-Lysosome Pathway for Induction of Autophagy",
"author": "Zhang",
"doi-asserted-by": "publisher",
"journal-title": "Oncotarget",
"key": "B24",
"volume": "7",
"year": "2016"
},
{
"DOI": "10.1080/15548627.2016.1179404",
"article-title": "A Novel Curcumin Analog Binds to and Activates TFEB In Vitro and In Vivo Independent of MTOR Inhibition",
"author": "Song",
"doi-asserted-by": "publisher",
"journal-title": "Autophagy",
"key": "B25",
"volume": "12",
"year": "2016"
},
{
"DOI": "10.3389/fncel.2021.777738",
"article-title": "SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy",
"author": "Datta",
"doi-asserted-by": "publisher",
"journal-title": "Front Cell Neurosci",
"key": "B26",
"volume": "15",
"year": "2021"
},
{
"DOI": "10.1038/s41598-019-48777-y",
"article-title": "BK Channels Regulate Extracellular Tat-Mediated HIV-1 LTR Transactivation",
"author": "Khan",
"doi-asserted-by": "publisher",
"first-page": "12285",
"journal-title": "Sci Rep",
"key": "B27",
"volume": "9",
"year": "2019"
},
{
"DOI": "10.1038/emboj.2011.286",
"article-title": "Endosome Maturation",
"author": "Huotari",
"doi-asserted-by": "publisher",
"journal-title": "EMBO J",
"key": "B28",
"volume": "30",
"year": "2011"
},
{
"DOI": "10.1146/annurev-physiol-012110-142317",
"article-title": "Lysosomal Acidification Mechanisms",
"author": "Mindell",
"doi-asserted-by": "publisher",
"first-page": "69",
"journal-title": "Annu Rev Physiol",
"key": "B29",
"volume": "74",
"year": "2012"
},
{
"DOI": "10.2741/4506",
"article-title": "Regulation of V-ATPase Activity",
"author": "Mcguire",
"doi-asserted-by": "publisher",
"journal-title": "Front Biosci (Landmark Ed)",
"key": "B30",
"volume": "22",
"year": "2017"
},
{
"DOI": "10.1074/jbc.RA118.002025",
"article-title": "Histone Deacetylase-Mediated Regulation of Endolysosomal pH",
"author": "Prasad",
"doi-asserted-by": "publisher",
"journal-title": "J Biol Chem",
"key": "B31",
"volume": "293",
"year": "2018"
},
{
"DOI": "10.1038/ncb0905-847",
"article-title": "The Lysosome Turns Fifty",
"author": "De Duve",
"doi-asserted-by": "publisher",
"journal-title": "Nat Cell Biol",
"key": "B32",
"volume": "7",
"year": "2005"
},
{
"DOI": "10.15252/embj.2021107821",
"article-title": "TMPRSS2 Expression Dictates the Entry Route Used by SARS-CoV-2 to Infect Host Cells",
"author": "Koch",
"doi-asserted-by": "publisher",
"first-page": "e107821",
"journal-title": "EMBO J",
"key": "B33",
"volume": "40",
"year": "2021"
},
{
"DOI": "10.1016/j.cell.2020.10.039",
"article-title": "Beta-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway",
"author": "Ghosh",
"doi-asserted-by": "publisher",
"first-page": "1520",
"journal-title": "Cell",
"key": "B34",
"volume": "183",
"year": "2020"
},
{
"DOI": "10.1126/science.abb2507",
"article-title": "Cryo-EM Structure of the 2019-Ncov Spike in the Prefusion Conformation",
"author": "Wrapp",
"doi-asserted-by": "publisher",
"journal-title": "Science",
"key": "B35",
"volume": "367",
"year": "2020"
},
{
"DOI": "10.1016/j.cell.2018.12.028",
"article-title": "Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion",
"author": "Walls",
"doi-asserted-by": "publisher",
"first-page": "1026",
"journal-title": "Cell",
"key": "B36",
"volume": "176",
"year": "2019"
},
{
"DOI": "10.1002/path.1570",
"article-title": "Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis",
"author": "Hamming",
"doi-asserted-by": "publisher",
"journal-title": "J Pathol",
"key": "B37",
"volume": "203",
"year": "2004"
},
{
"DOI": "10.1016/j.molcel.2020.04.022",
"article-title": "A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells",
"author": "Hoffmann",
"doi-asserted-by": "publisher",
"first-page": "779",
"journal-title": "Mol Cell",
"key": "B38",
"volume": "78",
"year": "2020"
},
{
"DOI": "10.1016/j.antiviral.2020.104792",
"article-title": "Coronavirus Membrane Fusion Mechanism Offers a Potential Target for Antiviral Development",
"author": "Tang",
"doi-asserted-by": "publisher",
"first-page": "104792",
"journal-title": "Antiviral Res",
"key": "B39",
"volume": "178",
"year": "2020"
},
{
"DOI": "10.1093/emboj/16.7.1508",
"article-title": "Activation of the Furin Endoprotease Is a Multiple-Step Process: Requirements for Acidification and Internal Propeptide Cleavage",
"author": "Anderson",
"doi-asserted-by": "publisher",
"journal-title": "EMBO J",
"key": "B40",
"volume": "16",
"year": "1997"
},
{
"DOI": "10.1242/jcs.083782",
"article-title": "Rab9-Dependent Retrograde Transport and Endosomal Sorting of the Endopeptidase Furin",
"author": "Chia",
"doi-asserted-by": "publisher",
"journal-title": "J Cell Sci",
"key": "B41",
"volume": "124",
"year": "2011"
},
{
"DOI": "10.1046/j.1432-1327.1999.00145.x",
"article-title": "Acidic pH as a Physiological Regulator of Human Cathepsin L Activity",
"author": "Turk",
"doi-asserted-by": "publisher",
"journal-title": "Eur J Biochem",
"key": "B42",
"volume": "259",
"year": "1999"
},
{
"DOI": "10.1083/jcb.90.3.656",
"article-title": "Cytoplasmic Vacuolation of Mouse Peritoneal Macrophages and the Uptake Into Lysosomes of Weakly Basic Substances",
"author": "Ohkuma",
"doi-asserted-by": "publisher",
"journal-title": "J Cell Biol",
"key": "B43",
"volume": "90",
"year": "1981"
},
{
"DOI": "10.1016/j.cellsig.2020.109706",
"article-title": "Janus Sword Actions of Chloroquine and Hydroxychloroquine Against COVID-19",
"author": "Chen",
"doi-asserted-by": "publisher",
"first-page": "109706",
"journal-title": "Cell Signal",
"key": "B44",
"volume": "73",
"year": "2020"
},
{
"DOI": "10.1038/s41421-020-0156-0",
"article-title": "Hydroxychloroquine, a Less Toxic Derivative of Chloroquine, is Effective in Inhibiting SARS-CoV-2 Infection In Vitro",
"author": "Liu",
"doi-asserted-by": "publisher",
"first-page": "16",
"journal-title": "Cell Discovery",
"key": "B45",
"volume": "6",
"year": "2020"
},
{
"DOI": "10.1038/s41422-020-0282-0",
"article-title": "Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus 2019-Ncov) In Vitro",
"author": "Wang",
"doi-asserted-by": "publisher",
"journal-title": "Cell Res",
"key": "B46",
"volume": "30",
"year": "2020"
},
{
"DOI": "10.1093/cid/ciaa237",
"article-title": "In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)",
"author": "Yao",
"doi-asserted-by": "publisher",
"journal-title": "Clin Infect Dis",
"key": "B47",
"volume": "71",
"year": "2020"
},
{
"DOI": "10.1001/jamainternmed.2020.6319",
"article-title": "Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-Exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial",
"author": "Abella",
"doi-asserted-by": "publisher",
"first-page": "195",
"journal-title": "JAMA Intern Med",
"key": "B48",
"volume": "181",
"year": "2021"
},
{
"DOI": "10.1056/NEJMoa2021801",
"article-title": "A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19",
"author": "Mitja",
"doi-asserted-by": "publisher",
"journal-title": "N Engl J Med",
"key": "B49",
"volume": "384",
"year": "2021"
},
{
"DOI": "10.1183/13993003.00752-2021",
"article-title": "Azithromycin and Hydroxychloroquine in Hospitalised Patients With Confirmed COVID-19: A Randomised Double-Blinded Placebo-Controlled Trial",
"author": "Sivapalan",
"doi-asserted-by": "publisher",
"first-page": "2100752",
"journal-title": "Eur Respir J",
"key": "B50",
"volume": "59",
"year": "2022"
},
{
"DOI": "10.1007/s00134-021-06448-5",
"article-title": "Lopinavir-Ritonavir and Hydroxychloroquine for Critically Ill Patients With COVID-19: REMAP-CAP Randomized Controlled Trial",
"author": "Arabi",
"doi-asserted-by": "publisher",
"journal-title": "Intensive Care Med",
"key": "B51",
"volume": "47",
"year": "2021"
},
{
"DOI": "10.7326/M20-6519",
"article-title": "Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial",
"author": "Barnabas",
"doi-asserted-by": "publisher",
"journal-title": "Ann Intern Med",
"key": "B52",
"volume": "174",
"year": "2021"
},
{
"DOI": "10.1002/mnfr.200700333",
"article-title": "Dimethoxycurcumin, A Synthetic Curcumin Analogue With Higher Metabolic Stability, Inhibits NO Production, Inducible NO Synthase Expression and NF-kappaB Activation in RAW264.7 Macrophages Activated With LPS",
"author": "Pae",
"doi-asserted-by": "publisher",
"journal-title": "Mol Nutr Food Res",
"key": "B53",
"volume": "52",
"year": "2008"
},
{
"DOI": "10.1016/j.pulmoe.2021.03.008",
"article-title": "The Immune Response to SARS-CoV-2 and COVID-19 Immunopathology - Current Perspectives",
"author": "Boechat",
"doi-asserted-by": "publisher",
"journal-title": "Pulmonology",
"key": "B54",
"volume": "27",
"year": "2021"
},
{
"DOI": "10.1073/pnas.2116853118",
"article-title": "A Virus-Specific Monocyte Inflammatory Phenotype is Induced by SARS-CoV-2 at the Immune-Epithelial Interface",
"author": "Leon",
"doi-asserted-by": "publisher",
"journal-title": "Proc Natl Acad Sci USA",
"key": "B55",
"volume": "119",
"year": "2022"
},
{
"DOI": "10.1111/acel.13069",
"article-title": "A Small Molecule Transcription Factor EB Activator Ameliorates Beta-Amyloid Precursor Protein and Tau Pathology in Alzheimer's Disease Models",
"author": "Song",
"doi-asserted-by": "publisher",
"journal-title": "Aging Cell",
"key": "B56",
"volume": "19",
"year": "2020"
}
],
"reference-count": 56,
"references-count": 56,
"relation": {},
"resource": {
"primary": {
"URL": "https://www.frontiersin.org/articles/10.3389/fviro.2022.923018/full"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "Dimethoxycurcumin Acidifies Endolysosomes and Inhibits SARS-CoV-2 Entry",
"type": "journal-article",
"update-policy": "http://dx.doi.org/10.3389/crossmark-policy",
"volume": "2"
}
