Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2008
Publication Date: 3/12/2009
Citation: Nachman, R.J., Teal, P.E., Ben-Aziz, O., Davidovitch, M., Zubrzak, P., Alstein, M. 2009. An amphiphilic, PK-PBAN analog is a selective pheromonotropic antagonist that penetrates the cuticle of a heliothine insect. Peptides. 30:616-621.
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. Nevertheless, natural neuropeptides are ineffective pest control agents because neuropeptides are susceptible to being degraded in the pest and are unable to penetrate the outside surface of pest insects. New control measures may be developed by designing metabolically stable mimics of these neuropeptides that interact with the active site within the agricultural or medical pest to either inhibit or over-stimulate critical life functions. We report on the development of versions of neuropeptides of the pyrokinin class that have been shown to selectively inhibit the production of sex pheromone. Furthermore, this paper reports that unlike the natural hormone, the inhibitor can penetrate the outside surface to reach the interior environment of an agriculturally important moth. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in selectively controlling pest arthropods in an environmentally friendly fashion.
Technical Abstract: A linear pyrokinin(PK)/pheromone biosynthesis activating neuropeptide (PBAN) lead antagonist was structurally modified to impart amphiphilic properties to enhance its ability to transmigrate the hydrophobic cuticle of noctuid moth species and yet retain aqueous solubility in the hemolymph to reach target PK/PBAN receptors within the internal insect environment. The resulting novel PK/PBAN analog, Hex-Suc-A[dF]PRLa (PPK-AA), was synthesized and evaluated as an antagonist in a pheromonotropic assay in Heliothis peltigera against 4 natural pyrokinin peptide elicitors (PBAN; pheromonotropin, Pss-PT; myotropin, MT; leucopyrokinin, LPK) and in a melanotropic assay in Spodoptera littoralis against three natural pyrokinin peptide elicitors (PBAN, PT, LPK). The analog proved to be a potent and efficacious inhibitor of sex pheromone biosynthesis elicited by PBAN (84 percent at 100 pmol) and PT (54 percent at 100 pmol), but not the latter two pyrokinin peptides. PPK-AA is a pure, selective antagonist as it failed to inhibit melanization elicited by any of the natural PK/PBAN peptides. The analog was shown to transmigrate isolated cuticle dissected from adult female Heliothis virescens moths to a high extent of 25-30% (130-150 pmol), representing physiologically significant quantities. PPK-AA represents a significant addition to the arsenal of tools available to arthropod endocrinologists studying the endogenous mechanisms of PK/PBAN regulated processes, and a prototype for the development of environmentally friendly pest management agents capable of disrupting the critical process of reproduction.