|JIANG, NONGBO - Kansas State University|
|WEI, ZHAOJUN - Kansas State University|
|KACZMAREK, KRZYSZTOF - Technical University Of Lodz|
|ZABROCKI, JANUSZ - Technical University Of Lodz|
|PARK, YOONSEONG - Technical University Of Lodz|
Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/12/2014
Publication Date: 5/15/2015
Citation: Jiang, N., Wei, Z., Nachman, R.J., Kaczmarek, K., Zabrocki, J., Park, Y. 2015. Functional characterization of five different PRXamide receptors of the red flour beetle Tribolium castaneum with peptidomimetics and identification of agonists and antagonists. Peptides. 68:246-252.
Interpretive Summary: Insect pests have developed resistance to several conventional pesticides, and new approaches are needed for pest management. Although neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, the neuropeptides hold little promise as pest control agents because they can be degraded in the target pest. New, selective control agents may be developed by designing mimics of these neuropeptides that resist degradation and either inhibit or over-stimulate critical neuropeptide-regulated life functions. We report on the characterization of five related active sites for a super-family of neuropeptide hormones that regulate such critical processes as development, water balance, overwintering, digestion, and reproduction in the red flour beetle, an important pest of stored grain. The work identified several strong, synthetic, stable mimics that either stimulate the active sites, or are able to selectively and/or non-selectively block the natural hormones from activating the active sites. This includes the first discovery of both selective and non-selective biostable agents able to block the water balance activity of hormones of the ‘CAPA’ class. This discovery, and the new information gained from it, will aid in the design of neuropeptide-like compounds capable of disrupting the survival mechanisms of these and related beetles. This may eventually lead to development of practical neuropeptide-like substances that can effectively control pest insects of stored grain in an environmentally friendly fashion.
Technical Abstract: The neuropeptidergic system in insects is considered to be an excellent target for pest control strategies. One promising biorational approach is the use of peptidomimetics modified from endogenous ligands to enhance biostability and bioavailability. In this study, we functionally characterized five different G protein-couple receptors in a phylogenetic cluster, containing receptors for PRXamide in the red flour beetle Tribolium castaneum, by evaluating a series of 70 different peptides and peptidomimetics. Three pyrokinin receptors (TcPKr-A, -B, and -C), cardioacceleratory peptide receptor (TcCAPAr) and ecdysis triggering hormone receptor (TcETHr) were included in the study. Strong agonistic or antagonistic peptidomimetics were identified, and included beta-proline (beta-3P) modification of the core amino acid residue proline and also a cyclo-peptide. A ligand acting on multiple receptors represents a common phenomenon. In a number of cases, a ligand acting as an agonist on one receptor was an efficient antagonist on another receptor, suggesting complex outcomes of a peptidomimetic in a biological system. Interestingly, TcPK-A was highly promiscuous with a high number of agonists, while TcPK-C and TcCAPAr had a lower number of agonists, but a higher number of compounds acting as an antagonist. This observation suggests that the target GPCR with more promiscuity will provide better success for peptidomimetic approaches. This study is the first description of peptidomimetics on a CAPA receptor and resulted in the identification of peptidomimetic analogs that demonstrate antagonism of CAPA (CAP2b) ligands. The PRXamide receptor assays with the peptidomimetics provide invaluable insights into the biochemical properties of receptors.