Title: Active diuretic peptidomimetic insect kinin analogs that contain Beta-turn mimetic motif 4-aminopyroglutamate and lack native peptide bonds Authors
|Kaczmarek, Krzysztof -|
|Zabrocki, Janusz -|
|Coast, Geoffrey -|
Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 28, 2011
Publication Date: March 15, 2012
Citation: Nachman, R.J., Kaczmarek, K., Zabrocki, J., Coast, G.M. 2012. Active diuretic peptidomimetic insect kinin analogs that contain Beta-turn mimetic motif 4-aminopyroglutamate and lack native peptide bonds. Peptides. 34:262-265. 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 have developed versions of neuropeptides of the ‘insect kinin’ class with enhanced resistance to degradation via a novel strategy that incorporates non-peptide components mimicking the 3D structure of the natural neuropeptide and with modified regions susceptible to degradation. Two of the neuropeptide versions have been shown to interact effectively to modulate the critical life process of water and mineral balance in a model insect, which may lead to development of practical neuropeptide-like substances that can effectively control pest insects in an environmentally friendly fashion.
Technical Abstract: The multifunctional arthropod 'insect kinins' share the evolutionarily conserved C-terminal pentapeptide core sequence Phe-X1-X2-Trp-Gly-NH2, where X1 = His, Asn, Ser, or Tyr and X2 = Ser, Pro, or Ala. Insect kinins regulate diuresis in many species of insects, including the cricket. Insect kinins, however, are susceptible to fast enzymatic degradation by endogenous peptidases that severely limit their use as tools for pest control or for endocrinological studies. To enhance resistance to peptidases, the core insect kinin sequence was structurally modified in this study to replace native peptide bonds susceptible to proteolytic degradation. These modifications include incorporation of two stereochemical variants of the beta-turn mimetic motif 4-aminogutamate in place of the X1-X2 residues, insertion of a reduced peptide bond between residues Trp-Gly, and replacement of the Phe residue with a hydrocinnamyl group. The resulting biostable, peptidomimetic analogs contain no native peptide bonds and yet retain significant diuretic activity in an in vitro cricket Malpighian tubule fluid secretion assay. These novel analogs represent ideal new tools for endocrinologists studying arthropod kinin regulated processes in vivo, and provide leads in the development of novel, environmentally friendly pest insect management agents capable of disruption of the critical processes that the insect kinins regulate.