Title : Next-generation alkaloid inhibitors against emerging and re-emerging flaviviruses and coronaviruses: A step toward broad-spectrum antivirals
Abstract:
Dengue virus (DENV) infects over 400 million people annually, yet no approved antiviral therapy exists and current vaccines provide limited serotype coverage. The increasing frequency and severity of outbreaks highlight the urgent need for effective broad-spectrum therapeutics. Natural alkaloids represent a promising but underexplored source of antiviral agents. Building on our previous identification of alkaloids active against coronaviruses and flaviviruses, we developed BB-0001, an optimized alkaloid-derived molecule with potent anti-dengue activity. BB-0001 inhibited DENV with an EC₅₀ of 0.47 µM and minimal cytotoxicity, demonstrating broad-spectrum efficacy against all four DENV serotypes (DENV1–4) and reducing viral RNA levels by >80%. Mechanistic and proteomic studies showed that BB-0001 blocks viral entry, suppresses RdRp-mediated replication, and enhances host antiviral signalling. In primary human macrophages, BB-0001 significantly reduced viral replication and pro-inflammatory cytokine production (IL-6, TNF-α). In AG129 mouse models, both prophylactic and therapeutic administration of BB-0001 (40 mg/kg) reduced viremia by >2–4 log₁₀ and prevented liver injury. Pharmacokinetic studies revealed good oral bioavailability, a moderate half-life (~6 h), and no observable toxicity up to 100 mg/kg. Collectively, BB-0001 is a potent alkaloid-derived dengue entry inhibitor with broad-spectrum activity against all four serotypes. Its combined antiviral and immunomodulatory effects, favourable pharmacokinetic profile, and robust in vivo efficacy support its potential as a first-in-class dengue antiviral candidate.
