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Title: Identifications of selective and non-selective, biostable beta-amino acid agonists of recombinant insect kinin receptors from the Southern cattle tick, Boophilus microplus, and mosquito, Aedes aegypti

item Taneja-bageshwar, Suparna
item Strey, Allison
item Zubrzak, Pawel
item Williams, Howard
item Reyes-rangel, Gloria
item Juaristi, Eusebio
item Pietrantonio, Patricia
item Nachman, Ronald - Ron

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/16/2007
Publication Date: 2/15/2008
Citation: Taneja-Bageshwar, S., Strey, A.A., Zubrzak, P., Williams, H., Reyes-Rangel, G., Juaristi, E., Pietrantonio, P., Nachman, R.J. 2008. Identifications of selective and non-selective, biostable beta-amino acid agonists of recombinant insect kinin receptors from the southern cattle tick, Boophilus microplus, and mosquito, Aedes aegypti. Peptides. 29:302-309.

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 insect kinin 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 potently with active sites in both the yellow fever mosquito and the cattle fever tick in a nonselective fashion. Two other versions have been shown to potently interact in a selective fashion with the active site in the cattle fever tick, and not that of the mosquito. Selectivity is an important component of successful and safe pest control methodologies. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest arthropods in an environmentally friendly fashion.

Technical Abstract: The multifunctional arthropod ‘insect kinins’ share the evolutionarily conserved C-terminal pentapeptide motif Phe-X1-X2-Trp-Gly-NH2, where X1 = His, Asn, Ser, or Tyr and X2 = Ser, Pro, or Ala. Eight different analogs of the insect kinin C-terminal pentapeptide active core in which the critical residues Phe1, Pro3 and Trp4 are replaced with beta-3-amino acid and/or their beta-2-amino acid counterparts were evaluated on recombinant insect kinin receptors from the southern cattle tick, Boophilus microplus (Canestrini) and the dengue vector, the mosquito Aedes aegypti (L.). A number of these analogs previously demonstrated enhanced resistance to degradation by peptidases. Single beta-2-Trp4 and double [beta-3-Phe2, beta-3-Pro3] replacement analogs of the insect kinins proved to be selective agonists for the tick receptor, whereas single-replacement beta-3-Pro3 and double-replacement [beta-3-Phe, beta-3-Pro3] analogs were strong agonists on both mosquito and tick receptors. These biostable analogs represent new tools for arthropod endocrinologists and potential leads in the development of selective, environmentally friendly arthropod pest control agents capable of disrupting insect kinin regulated processes.