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Title: A novel dihydromidazoline trans-Pro mimetic analog is a selective PK/PBAN agonist

item Nachman, Ronald
item Strey, Allison

Submitted to: Frontiers in Bioscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2009
Publication Date: 1/1/2010
Citation: Nachman, R.J., Ben-Aziz, O., Davidovitch, M., Kaczmarek, K., Zabrocki, J., Williams, H., Strey, A.A., Altstein, M. 2010. A novel dihydromidazoline trans-pro mimetic analog is a selective PK/PBAN agonist. Frontiers in Bioscience. E2:195-203.

Interpretive Summary: Because of problems with the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling insect pests. The basic premise of this research is that neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions. Nevertheless, neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest and an inability to penetrate the outside surface of pest insects. New, selective control measures may be developed by designing metabolically stable mimics of these neuropeptides that interact with the active site within the agricultural or medical pest in such a way as to either inhibit or over-stimulate critical neuropeptide-regulated life functions. We report on the development of versions of neuropeptides of the pyrokinin class that have been shown to selectively regulate the process of the coloration and hardening of the outer surface of insects, processes important for their defense. Selectivity is an important component of successful and safe pest control methodologies. The work was made possible due to the development of a new chemical construct/scaffold that mimics the 3-D structure of the natural neuropeptide and further enhances its biostability. 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/pheromone biosynthesis activating neuropeptide (PK/PBAN) family plays a significant role in the regulation of sex pheromone biosynthetic, melanization, pupariation and hindgut contractile processes in a variety of insects. Studies with restricted conformation analogs indicate that a transPro, type I beta-turn is an important aspect of the interaction of PK/PBAN peptides with their putative receptors. In this study, a PK/PBAN analog (PPK-Jo) incorporating a novel dihydroimidazole transPro mimetic motif was evaluated in four PK/PBAN bioassays; pheromonotropic in Heliothis peltigera, melanotropic in Spodoptera littoralis, pupariation in Neobellieria bullata, and hindgut myotropic in Leucophaea maderae. PPK-Jo proved to be a pure, selective melanotropic agonist in S. littoralis, showing no significant activity in the other three PK/PBAN bioassays. The melanotropic receptor in S. littoralis is apparently more promiscuous than those of the other PK/PBAN assays, demonstrating more tolerance to deviations from the transPro structure. The selective PK/PBAN agonist provides a new tool to better understand the endogenous mechanisms of this important peptide class and serves as a probe of the plasticity of PK/PBAN regulated systems and the their receptors. The work further demonstrates that the dihydroimidazoline moiety functions as a surrogate for a transPro in certain circumstances, and identifies a novel scaffold with which to construct mimetic PK/PBAN analogs with enhanced selectivity and the potential to disrupt critical physiological processes in insect pests.