Identification of antiviral antihistamines for COVID-19 repurposing
Leah R Reznikov, Michael H Norris, Rohit Vashisht, Andrew P Bluhm, Danmeng Li, Yan-Shin J. Liao, Ashley Brown, Atul J Butte, David A Ostrov
Biochemical and Biophysical Research Communications, doi:10.1016/j.bbrc.2020.11.095
a b s t r a c t There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Although repurposed drugs with favorable safety profiles could have significant benefit, widely available prevention or treatment options for COVID-19 have yet to be identified. Efforts to identify approved drugs with in vitro activity against SARS-CoV-2 resulted in identification of antiviral sigma-1 receptor ligands, including antihistamines in the histamine-1 receptor binding class. We identified antihistamine candidates for repurposing by mining electronic health records of usage in population of more than 219,000 subjects tested for SARS-CoV-2. Usage of diphenhydramine, hydroxyzine and azelastine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61. We found diphenhydramine, hydroxyzine and azelastine to exhibit direct antiviral activity against SARS-CoV-2 in vitro. Although mechanisms by which specific antihistamines exert antiviral effects is not clear, hydroxyzine, and possibly azelastine, bind Angiotensin Converting Enzyme-2 (ACE2) and the sigma-1 receptor as off-targets. Clinical studies are needed to measure the effectiveness of diphenhydramine, hydroxyzine and azelastine for disease prevention, for early intervention, or as adjuvant therapy for severe COVID-19.
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.bbrc.2020.11.095.
References
Basile, Paul, Mirchevich, Kuijpers, Costa, Modulation of (þ)-[3H]pentazocine binding to Guinea pig cerebellum by divalent cations, Mol. Pharmacol
Blyden, Greenblatt, Scavone, Shader, Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration, J. Clin. Pharmacol,
doi:10.1002/j.1552-4604.1986.tb02946.xCore, R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing
Cottam, Whelband, Wileman, Coronavirus NSP6 restricts autophagosome expansion, Autophagy,
doi:10.4161/auto.29309Derendorf, Munzel, Petzold, Bioavailability and disposition of azelastine and fluticasone propionate when delivered by MP29-02, a novel aqueous nasal spray, Br. J. Clin. Pharmacol,
doi:10.1111/j.1365-2125.2012.04222.xDyall, Gross, Kindrachuk, Middle east respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies, Drugs,
doi:10.1007/s40265-017-0830-1Fouda, Hobbs, Stambaugh, Sensitive assay for determination of hydroxyzine in plasma and its human pharmacokinetics, J. Pharmaceut. Sci
Freedberg, Conigliaro, Wang, Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study, Gastroenterology
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int. J. Antimicrob. Agents
Gordon, Jang, Bouhaddou, A SARS-CoV-2-Human Protein-Protein Interaction Map reveals Drug Targets and Potential Drug-repurposing, bioRxiv
Hernandez Prada, Ferreira, Katovich, Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents, Hypertension,
doi:10.1161/HYPERTENSIONAHA.107.108944Huentelman, Zubcevic, Hernandez Prada, Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor, Hypertension
Huentelman, Zubcevic, Hernandez Prada, Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor, Hypertension
Joshi, Joshi, Degani, Tackling SARS-CoV-2: proposed targets and repurposed drugs, Future Med. Chem,
doi:10.4155/fmc-2020-0147Liao, Kuan, Guevara, Acid exposure disrupts mucus secretion and impairs mucociliary transport in neonatal piglet airways, Am. J. Physiol. Lung Cell Mol. Physiol,
doi:10.1152/ajplung.00025.2020Lieberman-Cribbin, Rapp, Alpert, Tuminello, Taioli, The impact of asthma on mortality in patients with COVID-19, Chest
Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov,
doi:10.1038/s41421-020-0156-0Morris, Huey, Lindstrom, AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility, J. Comput. Chem,
doi:10.1002/jcc.21256Mossel, Huang, Narayanan, Makino, Tesh et al., Exogenous ACE2 expression allows refractory cell lines to support severe acute respiratory syndrome coronavirus replication, J. Virol
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
Rogosnitzky, Berkowitz, Jadad, Delivering benefits at speed through real-world repurposing of off-patent drugs: the COVID-19 pandemic as a case in point, JMIR Public Health Surveill,
doi:10.2196/19199Schmidt, Zheng, Gurpinar, Koehl, Manglik et al., Crystal structure of the human sigma1 receptor, Nature,
doi:10.1038/nature17391Towler, Staker, Prasad, ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis, J. Biol. Chem,
doi:10.1074/jbc.M311191200Vincent, Bergeron, Benjannet, Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol. J
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Yan, Zhang, Li, Xia, Guo et al., Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2, Science,
doi:10.1126/science.abb2762DOI record:
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"DOI": "10.1038/s41586-020-2286-9",
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"author": "Freedberg",
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"author": "Morris",
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"first-page": "2785",
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"key": "10.1016/j.bbrc.2020.11.095_bib19",
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"year": "2009"
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"DOI": "10.1038/nature17391",
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"article-title": "Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)",
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"key": "10.1016/j.bbrc.2020.11.095_bib22",
"series-title": "R: A Language and Environment for Statistical Computing",
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"author": "Mossel",
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"volume": "79",
"year": "2005"
},
{
"DOI": "10.1152/ajplung.00025.2020",
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"author": "Liao",
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"article-title": "Modulation of (+)-[3H]pentazocine binding to Guinea pig cerebellum by divalent cations",
"author": "Basile",
"first-page": "882",
"issue": "5",
"journal-title": "Mol. Pharmacol.",
"key": "10.1016/j.bbrc.2020.11.095_bib25",
"volume": "42",
"year": "1992"
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"author": "Fouda",
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"volume": "68",
"year": "1979"
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"author": "Berlin",
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