Rational design of dual PB2/JAK2 inhibitors achieving balanced antiviral and host-directed immunomodulatory effects

Infection with the influenza virus provokes an excessive immune reaction, triggering a cytokine storm that can cause severe inflammation and lead to conditions such as pneumonia and myocarditis. Herein, we propose a dual-target strategy that simultaneously targets the viral PB2 protein and the host JAK2 kinase, aiming to not only eliminate the virus but also modulate the immune response, facilitating rapid recovery of the body's health. In this article, the design and discovery of novel PB2/JAK2 dual-target inhibitors are reported. Through rational design and structure-guided optimization, we identified compound 4B, which exhibited potent anti-H1N1 activity (MDCK cell EC₅₀ = 15 nM) and JAK2 inhibitory activity (JAK2 IC₅₀ = 49 nM). Notably, 4B demonstrated favorable pharmacokinetic properties in mice, achieving excellent oral bioavailability (F = 99.4%). Furthermore, our findings show that compound 4B significantly downregulates NP and PB2 protein expression. Concurrently, 4B also inhibits the mRNA expression of key pro-inflammatory cytokines (IL-6, TNF-α, IFN-β) in both inflammatory and influenza-infected models. This study demonstrates the promising potential of dual inhibition, targeting both viral replication and the host inflammatory response, for the development of anti-influenza therapeutics.