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.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.
ABSTRACT
Acute myeloid leukemia (AML) is caused by clonal disorders of hematopoietic stem cells. Differentiation therapy is emerging as an important treatment modality for leukemia, given its less toxicity and wider applicable population, but the arsenal of differentiation-inducing agents is still very limited. In this study, we adapted a competitive peptide phage display platform to search for candidate peptides that could functionally induce human leukemia cell differentiation. A monoclonal phage (P6) and the corresponding peptide (pep-P6) were identified. Both L- and D-chirality of pep-P6 showed potent efficiency in inducing AML cell line differentiation, driving their morphologic maturation and upregulating the expression of macrophage markers and cytokines, including CD11b, CD14, IL-6, IL-1ß, and TNF-α. In the THP-1 xenograft animal model, administration of D-pep-P6 was effective in inhibiting disease progression. Importantly, exposure to D-pep-P6 induced the differentiation of primary human leukemia cells isolated AML patients in a similar manner to the AML cell lines. Further mechanism study suggested that D-pep-P6 induced human leukemia cell differentiation by directly activating a TLR-2 signaling pathway. These findings identify a novel D-peptide that may promote leukemia differentiation therapy.
