Discovery of a Cell-Permeable Gi-Signaling Inhibitor
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Heterotrimeric G proteins regulate diverse physiological processes, yet selective small molecule modulators for the Gα i subfamily remain scarce. Here, we employed native metabolomics to screen a fungal culture collection for G protein binders, which led to the discovery of N -hydroxyapiosporamide (NHAP), a fungal specialized metabolite that functionally inhibits Gi-signaling. NHAP selectively binds Gα i1 and diminishes Gα i1 -mediated GTP turnover in biochemical assays. In primary ventricular cardiomyocytes, NHAP largely reversed acetylcholine-induced negative inotropy, demonstrating functional Gi-signaling blockade in a physiological context without acute cytotoxicity. This work establishes NHAP as a first-in-class Gi-selective inhibitor, providing a cell-permeable chemical scaffold for the optimization of next-generation agents to control Gi-signaling in cell-based systems and, ultimately, to target Gα i1 -driven pathologies.
