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Title: Biostable beta-amino acid PK/PBAN analogs: Agonist and antagonist properties

item Nachman, Ronald
item Zubrzak, Pawel
item ISAAC, R
item Strey, Allison

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/15/2008
Publication Date: 3/12/2009
Citation: Nachman, R.J., Ben-Aziz, O., Davidovitch, M., Zubrzak, P., Isaac, R.E., Strey, A.A., Reyes-Rangel, G., Juaristi, E., Williams, H.J., Alstein, M. 2009. Biostable beta-amino acid PK/PBAN analogs: Agonist and antagonist properties. Peptides. 30:608-615.

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, neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest. New, selective 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 in such a way as to either inhibit or over-stimulate critical neuropeptide-regulated life functions. We report on the development of versions of neuropeptides of the ‘pyrokinin/PBAN’ 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 interact effectively to modulate a range of critical life processes in pest insects, including aspects of sex pheromone production, development, digestion and defensive mechanisms. 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: The pyrokinin/pheromone biosynthesis activating neuropeptide (PK/PBAN) family plays a significant role in a multifunctional array of important physiological processes in insects. PK/PBAN analogs incorporating beta-amino acids were synthesized and evaluated in a pheromonotropic assay in Heliothis peltigera, a melanotropic assay in Spodoptera littoralis, a pupariation assay in Neobellieria bullata, and a hindgut contractile assay in Leucophaea maderae. Two analogs (PK-betaA-1 and PK-betaA-4) demonstrate greatly enhanced resistance to the peptidases neprilysin and angiotensin converting enzyme that are shown to degrade the natural peptides. Despite the changes to the PK core, analog PK-betaA-4 represents a biostable, non-selective agonist in all four bioassays, essentially matching the potency of a natural PK in the pupariation assay. Analog PK-betaA-2 is a potent agonist in the melanotropic assay, demonstrating full efficacy at 1 pmol. In some cases, the structural changes imparted to the analogs modify the physiological responses. Analog PK-betaA-3 is a non-selective agonist in all four bioassays. The analog PK-betaA-1 shows greater selectivity than parent PK peptides; it is virtually inactive in the pupariation assay and represents a biostable antagonist in the pheromonotropic and melanotropic assays, without the significant agonism of the parent hexapeptide. These analogs provide new, and in some cases, biostable tools to endocrinologists studying similarities and differences in the mechanisms of the variety of PK/PBAN mediated physiological processes. They also may provide leads in the development of PK/PBAN-based, insect-specific pest management agents.