Identification of antiviral antihistamines for COVID-19 repurposing

• Published in: Biochemical and biophysical research communications Vol. 538; pp. 173 - 179
• Main Authors: Reznikov, Leah R., Norris, Michael H., Vashisht, Rohit, Bluhm, Andrew P., Li, Danmeng, Liao, Yan-Shin J., Brown, Ashley, Butte, Atul J., Ostrov, David A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.01.2021
• Subjects: adjuvants; Angiotensin converting Enzyme-2; Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animals; antihistamines; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; antiviral properties; Catalytic Domain; Chlorocebus aethiops; COVID-19 Drug Treatment; COVID-19 infection; disease prevention; Docking; Drug Repositioning; HEK293 Cells; Histamine Antagonists - chemistry; Histamine Antagonists - pharmacology; Histamine Antagonists - therapeutic use; Humans; Ligands; Protein Binding; Receptors, Histamine - chemistry; Receptors, sigma - chemistry; Repurposing; SARS-CoV-2; SARS-CoV-2 - drug effects; Severe acute respiratory syndrome coronavirus 2; Sigma-1 Receptor; telemedicine; therapeutics; Vero Cells; Docking; SARS-CoV-2; Angiotensin converting Enzyme-2; Repurposing; Sigma-1 receptor
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2020.11.095

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.