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Title: Bioavailabilty of beta-amino acid and C-terminally derived PK/PBAN analogs

item HARITON, ALIZA - Volcani Center (ARO)
item BEN-AZIZ, ORNA - Volcani Center (ARO)
item DAVIDOVITCH, MICHAEL - Volcani Center (ARO)
item ZUBRZAK, PAWEL - Pepceuticals Limited
item Nachman, Ronald
item ALTSTEIN, MIRIAM - Volcani Center (ARO)

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/12/2009
Publication Date: 7/15/2009
Citation: Hariton, A., Ben-Aziz, O., Davidovitch, M., Zubrzak, P., Nachman, R.J., Altstein, M. 2009. Bioavailabilty of beta-amino acid and C-terminally derived PK/PBAN analogs. Peptides. 30:2174-2181.

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 and inability to penetrate the outside surface of insects. 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. These variants have been further shown to efficiently penetrate the insect surface and one shows significantly greater longevity of action than the natural neuropeptides. These neuropeptide versions have also 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 ability of linear beta amino-acid-substituted peptides (PK-betaA-1: Ac-YFT[beta3-P]RLa; PK-betaA-2: Ac-Y[beta2-homoF]TPRLa; PK-betaA-3: Ac-Y[beta3-F]TPRLa and PK-betaA-4: Ac-[beta3-F]FT[beta3-P]RLa) and unsubstituted analogs (Ac-YFTPRLa and YFTPRLa) of the pyrokinin(PK)/pheromone biosynthesis-activating neuropeptide (PBAN) family to penetrate the insect cuticle and exert biological activity, (i.e., stimulate sex pheromone biosynthesis), was tested by topical application on Heliothis peltigera moths. The present results clearly indicate that small linear synthetic peptides can penetrate the cuticle very efficiently by contact application and activate their target organ. The time response of the peptides applied in DDW and DMSO were tested and the activities of topically applied and injected peptides were compared. The results clearly indicate that PK-betaA-4 and PK-betaA-3 exhibited high bioavailability (ability to penetrate through the cuticle and exertion of bioactivity) with the latter showing longer persistence in both solvents than any other analog in the study; indicative that incorporation of a beta-amino acid at the Phe1 position can enhance longevity in topical PK/PBAN analogs. PK-betaA-4 was significantly more active in DMSO than in DDW, and significantly more active than the parent peptide LPK in DMSO. PK-betaA-1 and PK-betaA-2 exhibited negligible activity. Interestingly, Ac-YFTPRLa was highly potent in both solvents; its activity in DDW did not differ from that of PK-betaA-4 and PK-betaA-3, and was higher than that of LPK. Even the unacylated peptide YFTPRLa was active in both solvents, at a similar level to LPK. Topically applied PK-betaA-4 and Ac-YFTPRLa exhibited significantly higher activity than the injected peptides. PK-betaA-3 and YFTPRLa were equally potent in both routes of administration.