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Title: Insect kinin analogs with cis-peptide bond motif 4-aminopyroglutamate: Optimal stereochemistry

Author
item KACZMAREK, KRZYSZTOF - TECH UNIV, POLAND
item COAST, GEOFFREY - UNIV OF LONDON
item WILLIAMS, HOWARD - TEXAS A&M UNIV
item ZABROCKI, JANUSZ - TECH UNIV, POLAND
item Nachman, Ronald

Submitted to: European Peptide Symposium
Publication Type: Proceedings
Publication Acceptance Date: 1/12/2007
Publication Date: 9/10/2007
Citation: Kaczmarek, K.J., Coast, G.M., Williams, H.J., Zabrocki, J., Nachman, R.J. 2007. Insect kinin analogs with cis-peptide bond motif 4-aminopyroglutamate: Optimal stereochemistry. In: Proceedings of the European Peptide Symposium, September 6-8, 2006, Gdansk, Poland. p. 116-117.

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. Neuropeptide mimics must be designed that resist degradation by enzymes in the digestive tract and blood of pest insects and interact with the active site within agricultural or medical pests by over-activating or blocking critical, neuropeptide-regulated life functions. We report on the identification of an optimal molecular scaffold to use in the design of biostable mimics of the insect kinin neuropeptide class, involved in the regulation of the critical process of water balance in insects. This work represents an important milestone and lead in the development of practical neuropeptide-like substances that will effectively control insect pests in an environmentally friendly fashion.

Technical Abstract: The insect kinins are present in a wide variety of insects and function as potent diuretic peptides, though they are subject to rapid degradation by internal peptidases. Insect kinin analogs incorporating stereochemical variants of (2S,4S)-4-aminopyroglutamate (APy), a cis-peptide bond motif, demonstrate significant activity in a cricket diuretic assay. Insect kinin analogs containing (2R,4R)-APy, (2S,4R)-APy and (2S,4S)-APy are essentially equipotent on an insect diuretic assay, with EC50 values of about 10-7M; whereas the (2R,4S)-APy analog is at least 10-fold more potent (EC50= 7 x 10-9M). Conformational studies in aqueous solution indicate that the (2R,4S)-APy analog is considerably more flexible than the other three variants, which may explain its greater potency. The work identifies the optimal stereochemistry for the APy scaffold with which to design biostable, peptidomimetic analogs with the potential to disrupt critical insect kinin-regulated processes in insects.