Cordycepin exhibits both antiviral and anti-inflammatory effects against dengue virus infection

Highlights•Cordycepin inhibits DENV-2 infection by over 1000-fold at 800 μM•Cordycepin suppresses DENV-induced cytokine/chemokine production•Cordycepin targets DENV NS5 protein, suppressing RANTES and hindering replication•NF-κB pathway involvement in cordycepin's anti-inflammatory action revealedSummaryCordycepin, a natural derivative of adenosine from Cordyceps militaris, can inhibit the replication of the dengue virus (DENV). Here, we investigated its antiviral and anti-inflammatory effects in DENV infected cells. Cordycepin significantly inhibited DENV-2 infection, virion production, and viral protein synthesis. It also reduced DENV-induced cytokine/chemokine production, including RANTES, IP-10, IL-6, and TNF-α. Mechanistically, cordycepin targeted the DENV NS5 protein, suppressing RANTES expression and hindering viral replication. Additionally, it inhibited the NF-κB pathway, leading to reduced nuclear translocation and signaling deactivation. PCR array analysis revealed cordycepin's suppression of 46 genes associated with DENV-induced inflammation. These findings highlight cordycepin's dual potential as an antiviral and anti-inflammatory agent against DENV, making it as a promising candidate for dengue treatment, targeting both viral and host factors.