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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.IMPORTANCEIn 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.

除了人类血管紧张素转换酶 2（hACE2）之外，许多宿主因素已被确定为严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的辅助受体，表明其具有广泛的病毒嗜性和多样化的可药物靶标。我们和其他人发现，抗组胺药物，特别是组胺受体 H1（HRH1）拮抗剂，能有效抑制 SARS-CoV-2 感染。在这项研究中，我们提供了令人信服的证据，表明 HRH1 通过直接结合病毒刺突蛋白，作为 SARS-CoV-2 的替代受体发挥作用。HRH1 还通过与 hACE2 相互作用，协同增强 hACE2 依赖性病毒进入。抗组胺药物通过竞争性结合 HRH1 有效阻止病毒感染，从而破坏刺突蛋白与其受体之间的相互作用。多种抑制试验表明，抗组胺药物广泛抑制各种 SARS-CoV-2 突变体的感染，平均 IC50 为 2.4µM。真实的 SARS-CoV-2 感染试验和人源化小鼠攻毒实验进一步证实了这些药物的预防作用，表明抗组胺药物在对抗 2019 年冠状病毒病方面具有治疗潜力。

重要性

除了人类血管紧张素转换酶 2 之外，严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）还可以利用替代辅助因子来促进病毒进入。在这项研究中，我们发现组胺受体 H1（HRH1）不仅是 SARS-CoV-2 的独立受体，还可以通过直接与 ACE2 相互作用，协同增强 ACE2 依赖性病毒进入。进一步的研究表明，HRH1 通过直接结合刺突蛋白的 N 端结构域促进 SARS-CoV-2 的进入。相反，抗组胺药物，主要是 HRH1 拮抗剂，可以与 HRH1 竞争结合，从而阻止病毒进入。这些发现表明，重新利用抗组胺药物进行给药可能是对抗 2019 年冠状病毒病的一种治疗干预措施。