1a.Objectives (from AD-416):
The general objective of this proposed work is to develop rationally designed mimetic antagonists (and agonists) of the pyrokinin(PK)/pheromone biosynthesis activating neuropeptide (PBAN) neuropeptide (Np) class with enhanced biostability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents.
1b.Approach (from AD-416):
This work will: . 1)develop an antagonist biophore by characterizing the conformation of previously developed cyclic antagonists;. 2)design and synthesize non-peptide antagonists incorporating appropriate cis/trans-Pro mimetic motifs as determined in 1;. 3)develop an arsenal of topically active PK/PBAN antagonists with an array of different time-release profiles;. 4)develop orally active PK/PBAN antagonists; and. 5)develop both rationally designed small molecule non-peptide libraries based on the antagonist biophore determined in 1, and evaluate them in receptor binding and cloned receptor assays. The work will validate PK/PBAN receptors as pest management targets, and provide important practical information for the further design and generation of new, small, non-peptide insecticide prototypes aimed at disruption of key neuroendocrine physiological functions in pest insects.
The goal of the project is to develop and exploit insect neuropeptide (NP) technology leading to more effective and environmentally friendly methods for pest arthropod control. Development of technology based on NP of the PK/PBAN (pyrokinin/pheromone biosynthesis activating neuropeptide) superfamily requires an understanding of the specific structures of PK-like NPs native to target arthropod pests and their location within the nervous system. In FY 2013, studies were completed to identify and map NPs of the PVK/CAP2b (periviscerokinin/ cardioacceleratory) NP class, PK/PBAN-like peptides that regulate myotropic and diuretic activity in the nervous systems of the cotton fleahopper, as well as in several disease vectors, including the deer tick, yellow fever mosquito, and the sand fly. Over the life of this project, the first active site for an antidiuretic hormone (a PVK/CAP2b receptor) in an insect (the assassin bug) was identified, and structural requirements for successful interaction between hormone and active site were defined (published in high-impact PNAS journal). The first PVK/CAP2b and PK active sites were also identified in the cattle fever tick, a disease vector for cattle. Project work developed versions of neuropeptides of the diapause hormone (DH) class, a member of the PK NP superfamily, with enhanced biostability that are much more active than DH in breaking diapause in the corn earworm. Unlike native DH, one such novel compound was identified that prevents the entry into pupal diapause when administered to the preceding larval stage of heliothine (e.g., corn earworm, tobacco budworm) insects, inducing the insect to commit a form of 'ecological suicide' (published in high-impact PNAS journal). Project work has resulted in publication of a total of 16 papers in peer-reviewed journals. Another half-dozen manuscripts are in preparation and will be submitted over the next several months. Research conducted under this project has significantly added to the scientific foundation necessary for ultimate development of effective and practical neuropeptide-based insect control agents that will act within living insects to disrupt critical life processes and with minimal or no adverse environmental effects.