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Title: Active peptidomimetic insect kinin analogs with type VI turn motif 4-aminopyroglutamate lack native peptide bonds

item KACZMAREK, KRZYSZTOF - Technical University Of Lodz
item COAST, GEOFFREY - University Of London
item ZABROCKI, JANUSZ - Technical University Of Lodz
item Nachman, Ronald

Submitted to: European Peptide Symposium
Publication Type: Proceedings
Publication Acceptance Date: 10/22/2010
Publication Date: 11/24/2010
Citation: Kaczmarek, K., Coast, G.M., Zabrocki, J., Nachman, R.J. 2010. Active peptidomimetic insect kinin analogs with type VI turn motif 4-aminopyroglutamate lack native peptide bonds. European Peptide Symposium. p. 422-423.

Interpretive Summary: Because of problems with the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling insect pests. The basic premise of this research is that neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions. Nevertheless, neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest. New, selective control measures may be developed by designing metabolically stable mimics of these neuropeptides that interact with the active site within the agricultural or medical pest in such a way as to either inhibit or over-stimulate critical neuropeptide-regulated life functions. We report on the development of versions of neuropeptides of the ‘insect kinin’ class with enhanced biostability via a novel strategy that involves incorporation of non-peptide components that mimic the 3D structure of the natural neuropeptide and modify regions that are susceptible to metabolic 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. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest insects in an environmentally friendly fashion.

Technical Abstract: Two stereochemical variant insect kinin mimetic analogs 1796 and 1797 containing (2S,4S)-APy (APy) and (2R,4S)-APy (Apy), respectively, were synthesized and evaluated on isolated Malpighian tubules of the house cricket Acheta domesticus to determine if they could retain the fluid secretion stimulatory effects of the natural insect kinins and parent APy analogs. Despite the major structural modifications present in these mimetic analogs in comparison with the natural insect kinins, the two biostable analogs retained significant diuretic activity on the cricket Malpighian tubule fluid secretion assay.