The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2
Fei Yu, Xiaoqing Liu, Hailan Ou, Xinyu Li, Ruxin Liu, Xi Lv, Shiqi Xiao, Meilin Hu, Taizhen Liang, Tao Chen, Xuepeng Wei, Zhenglai Zhang, Sen Liu, Han Liu, Yiqiang Zhu, Guangyan Liu, Tianyong Tu, Peiwen Li, Hui Zhang, Ting Pan, Xiancai Ma
mBio, doi:10.1128/mbio.01088-24
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.
IMPORTANCE 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. KEYWORDS SARS-CoV-2, receptor, HRH1, antihistamine, spike, viral entry T he coronavirus disease 19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has persistently threatened public health (1, 2). In addition to SARS-CoV-2, influenza virus (IFV) and respiratory syncytial virus have concurrently circulated within human society. The development of potent polyvalent vaccines or antibody cocktails to prevent this "tripledemic" is urgently needed. However, both SARS-CoV-2 and IFV undergo multiple rounds of immune evasion and enhanced transmissibility, which significantly decreases the effectiveness of vaccines or antibodies targeting ancestral strains. Recently, a newly emerged SARS-CoV-2 Omicron lineage, designated JN.1, has started to prevail worldwide (3). Although the ACE2 binding affinity
Surface plasmon resonance The binding affinities of HRH1 for hACE2 and SARS-CoV-2 S (D614G) were determined by surface plasmon resonance with a Biacore 8K + instrument (Cytiva). Briefly, the aforemen tioned purified hACE2-ECD and S-8M-ECD proteins were immobilized on Flow Cell 2 (FC2) of the CM5 sensor chip utilizing an amine coupling kit. Flow Cell 1 (FC1), which was not loaded with ligand proteins, was treated as the reference surface. Serially diluted HRH1 proteins at concentrations ranging from 81.25 to 3,000 nM were injected over both FC1 and FC2 at a flow rate of 30 µL/min. For each cycle, the contact time was set to 120 s, while the dissociation time was set to 300 s. The binding affinity of hACE2 for S was also monitored as a positive control. The concentration range, flow rate, contact time, and dissociation time of hACE2-ECD were the same as those of the HRH1 proteins. Response units (RUs) were calculated by subtracting responses of the reference channel (FC1) from responses of the active channel (FC2). Adjusted RUs were fitted to a 1:1 binding model utilizing Biacore insight evaluation software version 4.0.8.19879 (Cytiva). Both the association rate ("on rate", Ka) and dissociation rate ("off rate", Kd) were measured and analyzed. The equilibrium dissociation constant ("binding constant", KD) was calculated by dividing Ka by Kd (Kd/Ka).
Authentic virus infection assay The inhibitory effects of the antihistamines were confirmed via an..
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'abstract': '<jats:title>ABSTRACT</jats:title>\n'
' <jats:sec>\n'
' <jats:title/>\n'
' <jats:p>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.</jats:p>\n'
' <jats:sec>\n'
' <jats:title>IMPORTANCE</jats:title>\n'
' <jats:p>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.</jats:p>\n'
' </jats:sec>\n'
' </jats:sec>',
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'title': 'The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2',
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