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Insects impact human health through vector-borne diseases and cause major economic losses by damaging crops and stored agricultural products. Insect-specific growth regulators represent attractive control agents because of their safety to the environment and humans. We identified plant compounds that serve as juvenile hormone antagonists (PJHANs). Using the yeast twohybrid system transformed with the mosquito JH receptor as a reporter system, we demonstrate that PJHANs affect the JH receptor, methoprene-tolerant (Met), by disrupting its complex with CYCLE or FISC, formation of which is required for mediating JH action. We isolated five diterpene secondary metabolites with JH antagonist activity from two plants: Lindera erythrocarpa and Solidago serotina. They are effective in causing mortality of mosquito larvae at relatively low LD 50 values. Topical application of two diterpenes caused reduction in the expression of Met target genes and retardation of follicle development in mosquito ovaries. Hence, the newly discovered PJHANs may lead to development of a new class of safe and effective pesticides. Diseases transmitted by insects result in a million deaths per year (1), and insect infestation leads to annual losses of agricultural products worth billions of US dollars (2). The high toxicity of currently available insecticides presents environmental and health risks, and growing resistance and cross-resistance of insects to these existing insecticides gravely complicates the situation. Hence, there is an urgent need to develop novel effective insecticides.Insect growth regulators (IGRs) have been devised based on insect-specific functions. Three major classes of IGRs are commercially available (3). These IGRs include juvenile hormone (JH) agonists (methoprene and pyriproxyfen), ecdysone agonists (halofenozide and tebufenozide), and chitin synthase inhibitors (buprofezine). They possess low off-target toxicity and environmental danger and have been used to control pests. JHbased IGRs are of particular interest because JH is an insectspecific hormone. JH agonists (JHAs) disrupt insect endocrine regulation, causing abnormal development and larval fatality (4). However, JHAs have limitations in the scope of their applications because they mimic and enhance the JH mode of action. Theoretically, JH antagonists (JHANs) could be used as a powerful alternative, but no effective JHANs have yet been developed.Recent studies identified methoprene-tolerant (Met) as the JH receptor (5, 6). Met is a member of the family of basic helixloop-helix (bHLH)-Per-Arnt-Sim (PAS) transcription factors that requires homo-or heterodimerization for DNA binding and transcriptional regulation (7). In the Aedes aegypti mosquito, Met forms a heterodimer with other bHLH-PAS factors, the steroid receptor coactivator (SRC/FISC), or Cycle (CYC) in a JHdependent manner (8, 9). JH-mediated Met-CYC binding has been quantitatively simulated using the two-hybrid yeast β-galactosidase assay in a yeast cell, Y187 (9). Thus, it is possible to test both J...

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