Evaluation of a PK/PBAN Analog with an (E)-Alkene, trans-Pro Isostere Identifies the Pro Orientation for Activity in Four Diverse PK/PBAN Bioassays

The pyrokininpheromone biosynthesis activating neuropeptide PKPBAN family plays a multifunctional role in an array of important physiological processes in a variety of insects. An active core analog containing an E-alkene, trans-Pro isosteric component was evaluated in four disparate PKPBAN bioassays in four different insect species. These bioassays include pheromone biosynthesis in the moth Heliothis peltigera, melanization in the larval Spodoptera littoralis, pupariation acceleration in the larval fly Neobellieria bullata, and hindgut contraction in the cockroach Leucophaea maderae. The conformationally constrained analog demonstrated activity equivalent to parent PKPBAN peptides of equal length in all four PKPBAN bioassays, and matched andor approached the activity of peptides of natural length in three of them. In the melanization bioassay, the constrained analog exceeded the efficacy maximal response of the natural PBAN1-33 by a factor of 2 at 1 nmol. The results provide strong evidence for the orientation of Pro and the core conformation adopted by PKPBAN neuropeptides during interaction with receptors associated with a range of disparate PKPBAN bioassays. The work further identifies a scaffold with which to design mimetic PKPBAN analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting PKPBAN regulated systems.