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Title: ACTIVE CONFORMATION AND PEPTIDASE RESISTANCE OF CONFORMATIONALLY RESTRICTEDANALOGUES OF THE INSECT ALLATOSTATIN NEUROPEPTIDE FAMILY

Author
item Nachman, Ronald
item MOYNA, G - TEXAS A&M UNIVERSITY
item WILLIAMS, H - TEXAS A&M UNIVERSITY
item GARSIDE, C - UNIVERSITY OF TORONTO
item TOBE, S - UNIVERSITY OF TORONTO

Submitted to: Book Chapter
Publication Type: Book / Chapter
Publication Acceptance Date: 11/16/1997
Publication Date: N/A
Citation: N/A

Interpretive Summary: Insect neuropeptides of the allatostatin family are short chains of amino acids (the building blocks of proteins) that regulate developmental and reproductive processes critical for insect survival. Nevertheless, these insect neuropeptides in and of themselves hold little promise as insect control agents because of their susceptibility to being degraded in the target insect, instability under environmental conditions, and inability t pass through the outside skin (cuticle) of the insect. In this paper, we report on the determination of the three dimensional shape that the neuropeptide adopts in order to successfully operate within the insect. This knowledge was utilized to design and develop active mimics of the neuropeptides that are resistant to the processes that normally would degrade and destroy them within the insect. This work leads us one step closer to the development of practical neuropeptide-like chemicals that will be effective in controlling certain pest insects in an environmentall friendly fashion.

Technical Abstract: The allatostatins are involved in the regulation of juvenile hormone production, and are therefore critical to the maintenance of normal developmental and reproductive processes in insects. In this paper, we report the design, synthesis, biological evaluation and secondary structure of a series of linear mimetic allatostatin analogues containing conformationally restricted components within the active core sequence. Molecular dynamics analyses incorporating distance and angle constraints obtained from solution NMR spectra of the analogues provide strong evidence that the allatostatins adopt a beta-turn in the C-terminal pentapeptide core region during successful interaction with the receptor site. These analogues also demonstrate improved resistance to both hemolymph and tissue-bound peptidases that inactivate the native peptides. The information led to the design and development of a short, active allatostatin analogue that demonstrates complete resistance to both hemolymph and tissue-bound peptidases. Disruption of critical reproductive and developmental processes by mimetic analogues impervious to peptidase degradation could provide the basis for novel, selective and environmentally friendly pest insect management strategies in the future.