Inhibitory activity and mechanism of a scorpion-derived peptide BmKDfsin3 against SFTSV and HSV-1

ABSTRACT Antiviral peptides, as an important source of antiviral drugs, will have significant application value and potential in the field of viral prevention and treatment. Therefore, it is of great significance to discover broad-spectrum, highly efficient, and low-toxicity antiviral peptides. Here, we found that the scorpion venom peptide BmKDfsin3 not only concentration-dependently inhibited the replication of severe fever with thrombocytopenia syndrome virus (SFTSV) but also suppressed the replication of herpes simplex virus type 1 (HSV-1) in A549 cells. The results of antiviral phase assays showed that BmKDfsin3 mainly inhibited the post-entry stage of the life cycle of these two viruses. Mechanistically, BmKDfsin3 effectively suppressed the activation of p38 induced by SFTSV and HSV-1 infections. Furthermore, using poly(I:C) as a viral mimic, we found that BmKDfsin3 enhanced type I and III interferon signaling pathways by activating the transcription factors p52 and IRF3. Importantly, BmKDfsin3 exhibited good biosafety, including low cytotoxicity, hemolytic activity, and mouse toxicity. Overall, BmKDfsin3 was revealed to be a natural bioactive peptide with good biological safety, potent antiviral activity, and a broad antiviral spectrum. IMPORTANCE The scorpion venom peptide BmKDfsin3 mediates antiviral activity through a dual mechanism: it limits viral replication by inhibiting the exploitation of host p38 signaling by SFTSV and HSV-1, and it promotes host immune responses by activating transcription factors p52 and IRF3 to enhance type I and III interferon (IFN) signaling. This synergy between “inhibiting virus-dependent pathway” and “activating host immunity” confers potent, broad-spectrum antiviral activity upon BmKDfsin3, resulting in significant dose-dependent inhibition against phylogenetically distinct RNA (SFTSV) and DNA (HSV-1) viruses. Importantly, the peptide exhibits minimal cytotoxicity, hemolytic activity, and in vivo toxicity. This study provides new insights into how a single-peptide molecule achieves efficient, broad-spectrum antiviral activity by concurrently targeting virus-dependent and host immune pathways, highlighting the therapeutic potential of antiviral peptides in broad-spectrum drug design.