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Title: Enhanced oral availability/activity of a peptidase-resistant amphiphilic OIC analog of the pyrokinin/PBAN neuropeptides

item Nachman, Ronald
item Teal, Peter

Submitted to: European Comparative Endocrinologists
Publication Type: Proceedings
Publication Acceptance Date: 10/22/2002
Publication Date: 11/15/2002
Citation: Nachman, R.J., Teal, P.E. 2002. Enhanced oral availability/activity of a peptidase-resistant amphiphilic OIC analog of the pyrokinin/PBAN neuropeptides. Proceedings of European Comparative Endocrinologists. 23:2035-2043.

Interpretive Summary: Neuropeptides are short chains of amino acids (the building blocks of proteins) that regulate aspects of reproduction, development and digestion that are critical for insect survival. Nevertheless, these insect peptides in and of themselves hold little promise as insect control agents because of susceptibility to being degraded in the target insect, and inability to pass through the outside skin (cuticle) and/or digestive tract of the insect. We report on the identification of portions of the peptide susceptible to inactivation by enzymes within target insects and the development of an analog (mimic) that both fortify these sites and imparts a soapy quality. The resulting analog is capable of retaining oral activity, a characteristic lacking in the natural hormones. The results are the first to demonstrate oral activity of insect neuropeptide analogs that approximate activity of the natural hormone administered via injection. The work further delineates that those analogs that preferentially penetrate the foregut region, as opposed to the midgut region, demonstrate superior oral activity. The knowledge will be utilized to design and develop potent, orally-active mimics capable of disrupting reproduction, development and/or digestion in target insects. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling certain pest insects in an environmentally friendly fashion.

Technical Abstract: The amphiphilic, Oic analog 904 proves to be a superior tissue-bound peptidase-resistant pyrokinin/PBAN analog for oral administration, producing a pheromone spike in adult H. virescens at 3h post-ingestion of 60% of the maximal titer of injected PBAN. The native hormone PBAN is inactive via oral administration. The analog 904 readily penetrates a ligated foregut preparation, but is less effective in the ligated midgut. The success of the analog 904 may be a result of its ability to effectively penetrate the cuticular component of the foregut, thereby bypassing the hostile environment of the midgut.