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Title: CIS-PEPTIDE BOND MIMETIC TETRAZOLE ANALOGS OF THE INSECT KININS IDENTIFY THE ACTIVE CONFORMATION

Author
item Nachman, Ronald
item ZABROCKI, JANUSZ - TECH UNIV OF LODZ, POLAND
item OLCZAK, JACEK - TECH UNIV OF LODZ, POLAND
item WILLIAMS, HOWARD - DEPT OF CHEM, TAMU
item MOYNA, GUILLERMO - DEPT OF CHEM, TAMU
item SCOTT, A - DEPT OF CHEM, TAMU
item COAST, GEOFFREY - BIRKBECK COLLEGE, UK

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/24/2001
Publication Date: N/A
Citation: N/A

Interpretive Summary: Because of problems with the development of resistance to conventional insecticides, there is a critical need for new concepts and alternative approaches in controlling insect pests. Neuropeptides are short chains of amino acids that serve as potent internal messengers in insects to regulate vital functions. Neuropeptides are unsuitable for use in control measures because they degrade in the circulatory and digestive systems, and are unable to penetrate the outer surface of the insect. Selective control measures may be developed by designing metabolically stable mimics of these neuropeptides that actively inhibit or over-stimulate functions regulated by them, resulting in disruption of the internal environment of the insect. We used specialized chemical technology to identify the 3-D shape that the neuropeptide requires to regulate water balance within insects, and used this information to develop a neuropeptide mimic that can partially block the action of the natural hormone. This information is critical to efforts to produce control measures that can selectively disrupt insect life processes. This work leads us one step closer to the development of practical neuropeptide mimics that will effectively control certain pests in an environmentally friendly fashion.

Technical Abstract: The insect kinin neuropeptides have been implicated in the regulation of water balance, digestive organ contraction, and energy mobilization in a number of insect species. A previous solution conformation study of an active, restricted-conformation cyclic analog, identified two possible turn conformations as the likely active conformation adopted by the insect kinins at the receptor site. These were a cisPro type VI beta-turn over C-terminal pentapeptide core residues 1-4 and a transPro type I-like beta- turn over core residues 2-5, present in a ratio of 60:40. Synthesis and evaluation of the diuretic activity of insect kinin analogs incorporating a tetrazole moiety, which mimics a cis peptide bond, identifies the active conformation as the former. The discovery of a receptor interaction model can lead to the development of potent agonist and antagonist analogs of the insect kinins. Indeed, in this study a tetrazole analog with D stereochemistry has been shown to demonstrate partial antagonism of the diuretic activity of natural insect kinins, providing a lead for more potent and effective antagonists of this critical neuropeptide family. The future development of mimetic agonists and antagonists of insect kinin neuropeptides will provide important tools to neuroendocrinologists studying the mechanisms by which they operate and to researchers developing new, environmentally friendly pest insect control strategies.