Abstract

Plant viruses often manipulate host proteins to facilitate infection, but the molecular mechanisms underlying these interactions remain largely unclear. Here, we provide evidence that the cucumber mosaic virus (CMV) coat protein (CP) interacts with the host kinase CDPK7-like in Nicotiana benthamiana . In an overexpression system, this interaction facilitates liquid–liquid phase separation (LLPS), forming condensate-like structures that could influence host immune-related signalling. Strikingly, plants overexpressing the CDPK7-like gene exhibited significantly enhanced resistance against diverse viruses, including potato virus Y and pepper mild mottle virus, yet displayed heightened susceptibility to CMV, suggesting virus-specific hijacking. Notably, a coumarin-based small-molecule LLPS modulator D3 is developed, which selectively targets the critical Thr52 residue within CMV CP to rescue CDPK7-like from LLPS initiation. Stands in contrast to the commercial drug ribavirin (EC 50 = 195 μg/mL), D3 shows better inactivating property against CMV (EC 50 = 70.8 μg/mL). This study reveals a mechanism by which CMV manipulates a host factor through phase separation and contributes a promising lead compound D3 for strategies aimed at enabling plants to win pathogen battles.