|Nachman, Ronald - Ron|
Submitted to: Biopolymers
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/31/2006
Publication Date: 1/5/2007
Citation: Zubrzak, P., Williams, H., Coast, G.M., Isaac, R.E., Reyes-Rangel, G., Juaristi, E., Zabrocki, J., Nachman, R.J. 2007. Beta-amino acid analogs of an insect neuropeptide feature potent bioactivity and resistance to peptidase hydrolysis. Biopolymers. 88:76-82. 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. New, 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 report on the development of versions of neuropeptides of the insect kinin class with enhanced biostability via a novel strategy that involves use of non-natural variants of amino acids known as ‘beta’ amino acids. Two of the neuropeptide versions have been shown to be as potent as natural neuropeptides in terms of their ability to regulate water balance in insects. They have been further shown to be stable to internal insect factors that inactivate the natural neuropeptides. 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: Insect neuropeptides of the insect kinin class share a common C-terminal pentapeptide sequence F1X12X23W4G5-NH2 (X23 = P, S, A) and regulate such critical physiological processes as water balance and digestive enzyme release. Analogs of the insect kinin class, in which the critical residues of F1, P3 and W4 were replaced with beta3-amino acid and/or their beta2-homo-amino acid variants have been synthesized by the solid phase peptide strategy. The resulting single- and double-replacement analogs were evaluated in an insect diuretic assay and enzyme digestion trials. Analogs modified in the core P3 position produce a potent and efficacious diuretic response that is not significantly different from that obtained with the endogenous achetakinin peptides. The analogs also demonstrate enhanced resistance to hydrolysis by ACE and NEP, endopeptidases that inactivate the natural insect neuropeptides. This paper describes the first instance of beta-amino acids analogs of an arthropod peptide that demonstrate significant bioactivity and resistance to peptidase degradation.