Could Histamine H1 Receptor Antagonists Be Used for Treating COVID-19?

Abstract

COVID-19 has rapidly become a pandemic worldwide, causing extensive and long-term health issues. There is an urgent need to identify therapies that limit SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Unbalanced lung inflammation is a common feature in severe COVID-19 patients; therefore, reducing lung inflammation can undoubtedly benefit the clinical manifestations. Histamine H1 receptor (H1 receptor) antagonists are widely prescribed medications to treat allergic diseases, while recently it has emerged that they show significant promise as anti-SARS-CoV-2 agents. Here, we briefly summarize the novel use of H1 receptor antagonists in combating SARS-CoV-2 infection. We also describe the potential antiviral mechanisms of H1 receptor antagonists on SARS-CoV-2. Finally, the opportunities and challenges of the use of H1 receptor antagonists in managing COVID-19 are discussed.

Keywords: COVID-19; H1 receptor antagonists; NF-κB signaling; drugs; treatment.

Figure 1

Schematic diagram presenting life cycle of SARS-CoV-2 and relevant inhibitors. SARS-CoV-2 cell entry begins with binding of the spike S protein to ACE2, a process that is facilitated by TMPRSS2. SARS-CoV-2 enters the cell through endocytosis, and then the virus is uncoated in the acidic environment of lysosomes. After that, SARS-CoV-2 RNA is released, followed by the reproduction of virus genome and viral proteins. Then, the viral components are assembled and released via exocytosis [15]. Each step can be targeted by relevant inhibitors. H1 receptor antagonists may inhibit SARS-CoV-2 either via H1 receptor or via ACE2 receptor. SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and ACE2 through its receptor-binding domain (RBD) [16]. H1 receptor antagonists may disrupt the interaction between heparan sulfate and spike protein, inhibiting SARS-CoV-2 entry.

Figure 2

The potential antiviral mechanisms of H1 receptor antagonists on SARS-CoV-2. SARS-CoV-2 infection leads to histamine release (A) and activates the NF-κB signaling (B), leading to enhancement of inflammatory response to facilitate its replication [81]. Histamine-mediated NF-κB signaling has been associated with the upstream phospholipase C (PLC) and protein kinase C (PKC) activation [82]. The activation of NF-κB by histamine can be blocked by H1 receptor antagonists [83]. H1 receptor antagonists may inhibit the NF-κB signaling through H1 receptor-dependent or -independent mechanisms [84].