Submitted to: Peptides
Publication Type: Peer reviewed journal
Publication Acceptance Date: 9/4/2002
Publication Date: 12/20/2002
Citation: NACHMAN,R.J., TEAL,P.E., STREY,A.A., ENHANCED ORAL AVAILABILITY/PHEROMOTROPIC ACTIVITY OF PEPTIDASE-RESISTANT TOPICAL AMPHIPHILIC ANALOGS OF PYROKININ/PBAN INSECT NEUROPEPTIDES, PEPTIDES, 2002. 23: 2035-2043 Interpretive Summary: Neuropeptides of the pyrikinin/PBAN family 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 their 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 the portions of the peptide susceptible to inactivation by enzymes within target insects and the development of analogs (mimics) that both fortify these sites and impart a soapy quality. The resulting analogs are capable of either retaining oral activity or penetration of the outer surface, characteristics lacking in the natural hormones. The results are the first to show that insect neuropeptide analogs can demonstrate oral activity that approximates that 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 a step closer to the development of practical neuropeptide-like chemicals that will be effective in controlling certain pest insects in an environmentally-friendly fashion.
Technical Abstract: The peptide bond between active core residues Pro and Arg is the primary site of susceptibility for the pyrokinin/PBAN neuropeptides to insect tissue-bound peptidases, and incorporation of modified Pro residues can enhance resistance to peptidase hydrolysis. An Hyp-containing amphiphilic analog is shown to operate as a topically active tissue-bound, peptidase-resistant analog of the pyrokinin/PBAN class of insect neuropeptides in adult H. virescens moths. An Oic amphiphilic analog is ineffective topically, but proves to be a superior tissue-bound, peptidase-resistant pyrokinin/PBAN analog for oral administration; outperforming both the Hyp analog and the orally-inactive natural hormone PBAN in the moths. The Oic analog is effective in penetrating an isolated, ligated foregut preparation, but less successful in transmigrating an isolated midgut preparation; whereas the opposite behavior is observed for the Hyp analog. The success of the Oic analog via oral administration may be related to its ability to effectively penetrate the foregut, thereby bypassing the hostile environment of the midgut region.