Histamine receptors and COVID-19

Abstract

Objective: Reports that the over-the-counter histamine H₂ receptor antagonist famotidine could help treat the novel coronavirus disease (COVID-19) appeared from April 2020. We, therefore, examined reports on interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and histamine receptor antagonists.

Methods: A systematic literature search was performed by 19 September 2020, and updated on 28 October 2020, in PubMed, Scopus, Cochrane Library and Google Scholar using (COVID-19 OR coronavirus OR SARS-CoV-2) AND (histamine antagonist OR famotidine OR cimetidine). ClinicalTrials.gov was searched for COVID-19 and (famotidine or histamine).

Results: Famotidine may be a useful addition in COVID-19 treatment, but the results from prospective randomized trials are as yet awaited. Bioinformatics/drug repurposing studies indicated that, among several medicines, H₁ and H₂ receptor antagonists may interact with key viral enzymes. However, in vitro studies have to date failed to show a direct inhibition of famotidine on SARS-CoV-2 replication.

Conclusions: Clinical research into the potential benefits of H₂ receptor antagonists in managing COVID-19 inflammation began from a simple observation and now is being tested in multi-centre clinical trials. The positive effects of famotidine may be due to H₂ receptor-mediated immunomodulatory actions on mast cell histamine-cytokine cross-talk, rather than a direct action on SARS-CoV-2.

Keywords: COVID-19; Histamine; Histamine receptor; Immunomodulation; Mast cells; SARS-CoV-2.

Fig. 1

Schematic presentation of the life cycle of SARS-CoV-2 in the host cell and proposed sites of famotidine action. The attachment and entry of the virus into the host cell (➊) require the interaction of angiotensin-converting enzyme 2 (ACE2) with the viral S glycoprotein, which is processed by the cellular transmembrane protease serine 2 (TMPRSS2). Following viral fusion with the target cell cytoplasmic membrane, the positive-sense single-stranded genomic RNA [(+)gRNA] of the virus is released into the host cytoplasm (➋) and the open reading frames (ORF) 1a and 1b are translated into the polyproteins pp1a and pp1ab (➌). These are cleaved by the viral papain-like (PL^pro) and 3C-like (3CL^pro) proteases to generate 16 non-structural proteins (nsps), including RNA-dependent RNA polymerase (RdRP), a core constituent of the replication–transcription complex (RTC) (➍). During replication (➎), the negative-sense genomic RNA [(−)gRNA] serves as template for the (+)gRNA, whereas the nested subgenomic RNAs [(+)sgRNA] produced by fragmented transcription through negative-strand intermediates [(−)sgRNA] (➎) are translated into the SARS-CoV-2 structural (➏) and accessory proteins. The nucleocapsids assembled from gRNA encapsidated by N protein and the structural proteins S, E and M inserted in the endoplasmic reticulum move along the secretory pathway (➐) and form mature virions that are transported to the cell surface in vesicles (➑) and released from the infected cell by exocytosis (➒) [7, 10, 11]. Bold arrows indicate the sites of action of the histamine H₂ receptor antagonist famotidine as proposed by computational studies [5, 36, 40], yet not experimentally confirmed [43, 51]