2012 Annual Report
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 this project is to develop and exploit insect neuropeptide (NP) technology to develop more effective and environmentally friendly methods for pest arthropod control, which requires an understanding of the specific structures of insect NPs native to target arthropod pests and their location within the nervous system. In FY 2012, studies were completed to identify and map NPs of the PVK/CAP2b (periviscerokinin/cardioacceleratory) NP class, peptides that regulate myotropic (muscle movement) and diuretic (water balance) activity in the nervous system of the cotton fleahopper (a crop pest); similar studies have been initiated in the boll weevil and in the Phlebotomus sand fly (a human disease vector). In FY 2012, project work identified a stereochemical characteristic of the antagonist biophore, an important step in the development of non-peptide analogs that block this important step in heliothine plant pests such as corn earworm. Also in FY 2012, project scientists studied several biostable PK/PBAN (pyrokinin/pheromone biosynthesis-activating neuropeptide) analogs that contain a modification known as PEGylation (attachment of polyethylene glycol polymer chains to NPs), a synthetic strategy designed to enhance bioavailability and cell-penetration characteristics. The PEGylated analogs were evaluated in a pea aphid feeding assay. The pea aphid causes hundreds of millions of dollars of crop damage every year, and a search for alternative strategies to control this pest is urgently needed. The biostable PK analogs demonstrated potent antifeedant activity, whereas unmodified, natural PKs were inactive. Two analogs featured activity that matched the potency of some commercially available aphicides. Notably, experiments demonstrated that the PK analogs act through a neuropeptide receptor (active site), a very selective mechanism. Accomplishments to date have 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.