Innate immunity is the front line of self-defense against microbial infection. After searching for natural compounds that regulate innate immunity using an ex vivo Drosophila culture system, we identified a new cyclic depsipeptide, aspergillicin F, from the fungus Aspergillus sp., as an innate immune suppressor. The total synthesis and biological evaluation of the aspergillicin family, including aspergillicin F, were performed, revealing that slight structural differences in the side chains of amino acid residues alter innate immunity-regulating activity.