Unique peptidic agonists of a juvenile hormone receptor with species-specific effects on insect development and reproduction

• DOI: 10.1073/pnas.2215541119
• Publication Date: 2022-11-21T20:18:11Z
• Authors: Sarka Tumova; Matej Milacek; Ivan Šnajdr; Magesh Muthu; Roman Tuma; David Reha; Pavel Jedlicka; Lenka Bittova; Adela Novotna; Pavel Majer; David Sedlak; Marek Jindra
• Keywords: Juvenile Hormones; Insecta; Reproduction; Larva; Animals; Female; Biological Sciences; Ligands; Methoprene; Peptides

Juvenile hormones (JHs) control insect metamorphosis and reproduction. JHs act through a receptor complex consisting of methoprene-tolerant (Met) taiman (Tai) proteins to induce transcription specific genes. Among chemically diverse synthetic JH mimics (juvenoids), some which serve as insecticides, unique peptidic juvenoids stand out being highly potent yet exquisitely selective family true bugs. Their mode action is unknown. Here we demonstrate that, like established agonists, upon the JHR Met halt in larvae linden bug, Pyrrhocoris apterus . Peptidic induced ligand-dependent dimerization between Tai from P. but, consistent with their selectivity, not other insects. A cell-based split-luciferase system revealed that Met–Tai assembled within minutes agonist presence. To explore potential juvenoid peptides, synthesized 120 new derivatives tested them interaction assays. While many substituents led loss activity, improved active at sub-nanomolar range outperformed hitherto existing classical including fenoxycarb. potency inducing corresponded capacity block stimulate oogenesis reproductively arrested adult females. Molecular modeling demonstrated high correlates affinity. This result malleability ligand-binding pocket allows larger ligands maximize contact surface. Our data establish species-selective novel agonists.