# The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2

## TL;DR

This study shows that the histamine receptor H1 can act as an alternative receptor for SARS-CoV-2 and that antihistamine drugs may help prevent infection.

## Contribution

The study identifies HRH1 as an alternative receptor for SARS-CoV-2 and shows antihistamines can inhibit viral entry.

## Key findings

- HRH1 directly binds to the SARS-CoV-2 spike protein and acts as an alternative receptor.
- Antihistamine drugs inhibit SARS-CoV-2 infection by competitively binding to HRH1.
- Antihistamines broadly inhibit various SARS-CoV-2 mutants with an average IC50 of 2.4 µM.

## Abstract

Numerous host factors, in addition to human angiotensin-converting enzyme 2
(hACE2), have been identified as coreceptors of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and
diversified druggable potential. We and others have found that antihistamine
drugs, particularly histamine receptor H1 (HRH1) antagonists, potently
inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence
that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding
to the viral spike protein. HRH1 also synergistically enhanced
hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs
effectively prevent viral infection by competitively binding to HRH1,
thereby disrupting the interaction between the spike protein and its
receptor. Multiple inhibition assays revealed that antihistamine drugs
broadly inhibited the infection of various SARS-CoV-2 mutants with an
average IC50 of 2.4 µM. The prophylactic function of these drugs was
further confirmed by authentic SARS-CoV-2 infection assays and humanized
mouse challenge experiments, demonstrating the therapeutic potential of
antihistamine drugs for combating coronavirus disease 19.

In addition to human angiotensin-converting enzyme 2, severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative
cofactors to facilitate viral entry. In this study, we discovered that
histamine receptor H1 (HRH1) not only functions as an independent
receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent
viral entry by directly interacting with ACE2. Further studies have
demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly
binding to the N-terminal domain of the spike protein. Conversely,
antihistamine drugs, primarily HRH1 antagonists, can competitively bind
to HRH1 and thereby prevent viral entry. These findings revealed that
the administration of repurposable antihistamine drugs could be a
therapeutic intervention to combat coronavirus disease 19.