trans-Pro isosteres in the development of non-selective and selective mimetic agonists of insect pyrokinin neuropeptides: A review

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 dihydroimidazoline 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.