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Title: Trans-Pro isosteres in the development of non-selective and selective mimetic insect pyrokinin neuropeptide agonists: A mini-review


Submitted to: Pestycydy/Pesticides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/28/2009
Publication Date: 11/16/2009
Citation: Nachman, R.J. 2009. Trans-pro isosteres in the development of non-selective and selective mimetic insect pyrokinin neuropeptide agonists: A mini-review. Pestycydy/Pesticides. 14:33-39.

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, these neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest, and inability to pass through the outside skin (cuticle) and/or digestive tract. We must design neuropeptide mimics that resist degradation by enzymes in the digestive tract and blood of pest insects and interact with the active site within the agricultural pest in such a way as to either over-activate or block critical, neuropeptide-regulated life functions. We review the development of two novel analog mimics of the ‘pyrokinin/PBAN’ neuropeptide class that clearly identify the 3-D structure adopted by the natural hormones at the active sites in a variety of insect species. In insects, pyrokinins regulate critical aspects of reproduction, development and digestion. The work further identifies new scaffolds with which to design and develop analogs with enhanced biostability and selectivity. These discoveries will aid in the design of neuropeptide-like compounds capable of disrupting the reproduction, development and digestion of pest insects. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest insects 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. A PK active core analog containing an (E)-alkene, transPro isosteric component was evaluated in five disparate PK bioassays and/or in a recombinant PK receptor cell line, representing six different insect species. The assays included pheromone biosynthesis in the moth Heliothis peltigera, melanization in the larval Spodoptera littoralis, pupariation acceleration in the larval fly Neobellieria bullata, diapause termination in the moth Heliothis zea, and hindgut contraction in the cockroach Leucophaea maderae. This constrained analog demonstrated unselective agonist activity that approached, matched, or exceeded the activity of parent PK peptides of equal length in all six PK assays. The results provide 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 transPro motif, the dihydorimidazoline moiety, was found to demonstrate pure, selective agonism in the melanotropic bioassay, with no significant activity in three other PK bioassays. Both types of transPro isosteric analogs feature modification adjacent to the primary tissue-bound peptidase hydrolysis site that is expected to enhance biostability over natural PK peptides. The research further identifies two novel scaffolds with which to design either selective or non-selective mimetic PK analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting PK-regulated systems.