Title: Development of an antogonist and selective agonist of insect pyrokinin neuropeptides with dihydroimidazole, a trans-Pro mimetic motif Author
Submitted to: Meeting Proceedings
Publication Type: Proceedings
Publication Acceptance Date: October 19, 2011
Publication Date: October 30, 2011
Citation: Nachman, R.J. 2011. Development of an antogonist and selective agonist of insect pyrokinin neuropeptides with dihydroimidazole, a trans-Pro mimetic motif. Proc. 2011 Int. Symp. Meeting of the Korean Soc. Appl. Biol., Chem. p. 99-102. Interpretive Summary: Insect pests have developed resistance to several conventional pesticides, and new approaches are needed for pest management. Although neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, the neuropeptides hold little promise as pest control agents because they can be degraded in the target pest. New, selective control agents may be developed by designing mimics of these neuropeptides that resist degradation and either inhibit or over-stimulate critical neuropeptide-regulated life functions. We report on the discovery of a unique strategy for the development of versions of neuropeptides of the pyrokinin class that can either selectively mimic or block neuropeptide actions that regulate an insect’s defense mechanisms. The work was made possible due to the development of a new chemical construct that mimics the 3-D structure of the natural neuropeptide and further enhances its stability against degradation. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest arthropods in an environmentally friendly fashion.
Technical Abstract: The pyrokinin (PK) family plays a multifunctional role in an array of important physiological processes in a variety of insects. The strong activity observed for a PK active core analog containing an (E)-alkene, transPro isosteric component in six disparate PK bioassay systems provided strong evidence for the orientation of Pro and the core conformation adopted by PK neuropeptides during interaction with disparate PK receptors. A PK active core analog incorporating a second, novel transPro motif, the dihydroimidazole moiety, was found to demonstrate pure, selective agonism in a melanotropic bioassay, with no significant activity in three other PK bioassays. A second PK core analog incorporating the dihydroimidazole moiety proved to be an antagonist of the diapause-termination activity of diapause hormone, a member of the PK superfamily of neuropeptides. Both of these dihydroimidazole analogs feature a modification adjacent to the primary tissue-bound peptidase hydrolysis site that is expected to enhance biostability over natural PK peptides. The research identifies a novel scaffold with which to design either selective-agonist or antagonist, mimetic PK analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting PK-regulated systems.