Identification of antiviral antihistamines for COVID-19 repurposing

Biochem Biophys Res Commun. 2021 Jan 29;538:173-179. doi: 10.1016/j.bbrc.2020.11.095. Epub 2020 Dec 3.

Abstract

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.

Keywords: Angiotensin converting Enzyme-2; Docking; Repurposing; SARS-CoV-2; Sigma-1 receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / chemistry*
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • COVID-19 / drug therapy*
  • Catalytic Domain
  • Chlorocebus aethiops
  • Drug Repositioning*
  • HEK293 Cells
  • Histamine Antagonists / chemistry*
  • Histamine Antagonists / pharmacology
  • Histamine Antagonists / therapeutic use
  • Humans
  • Ligands
  • Protein Binding
  • Receptors, Histamine / chemistry
  • Receptors, sigma / chemistry
  • SARS-CoV-2 / drug effects*
  • Vero Cells

Substances

  • Antiviral Agents
  • Histamine Antagonists
  • Ligands
  • Receptors, Histamine
  • Receptors, sigma
  • sigma-1 receptor
  • Angiotensin-Converting Enzyme 2