Location: Areawide Pest Management Research
Title: Biostable agonists that match or exceed activity of native insect kinins on recombinant arthropod GPCRs Authors
|Taneja-Bageshwar, Suparna - TEXAS A&M UNIV|
|Isaac, R - UNIV OF LEEDS, UK|
|Coast, Geoffrey - UNIV OF LONDON|
|Pietrantonio, Patricia - TEXAS A&M UNIV|
Submitted to: General and Comparative Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 6, 2008
Publication Date: May 15, 2009
Citation: Taneja-Bageshwar, S., Strey, A.A., Isaac, R.E., Coast, G.M., Zubrzak, P., Pietrantonio, P.V., Nachman, R.J. 2009. Biostable agonists that match or exceed activity of native insect kinins on recombinant arthropod GPCRs. General and Comparative Endocrinology. 162:122-128. 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 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 to either inhibit or over-stimulate critical 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 a non-natural amino acid variant known as Aib. One of the neuropeptide versions has been shown to interact more potently with active sites in both the yellow fever mosquito and the cattle fever tick than native hormones. These potent, biostable versions represent ideal new tools for scientists studying insect kinin regulated processes within living arthropods, particularly for ticks in which their role remains to be established. They also represent leads for agents that can disrupt insect kinin regulated processes in insect pests. 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. Insect kinins regulate diuresis in many species of insects. Compounds with similar biological activity could be exploited for the control of arthropod pest populations such as the mosquito Aedes aegypti (L.) and the southern cattle tick Rhipicephalus (Boophilus) microplus (Canestrini), vectors of human and animal pathogens, respectively. Insect kinins, however, are susceptible to fast enzymatic degradation by endogenous peptidases that severely limit their use as tools for pest control or for endocrinological studies. To enhance resistance to peptidases, analogs of the insect kinins incorporating bulky a,a-disubstituted amino acids in positions adjacent to both primary and secondary peptidase hydrolysis sites were synthesized. In comparison with a control insect kinin, several of the analogs are highly stable to hydrolysis by degradative enzymes ANCE, neprilysin and Leucine aminopeptidase. Six analogs were evaluated by calcium bioluminescence assay on recombinant receptors from mosquito and tick. Four of these analogs either matched or exceeded the potency of the control kinin peptide agonist. One of these was about five-fold more potent than the control agonist on the tick receptor. This analog was eight-fold more potent than the control agonist on the mosquito receptor, and twice more potent than the endogenous Aedes kinin II. The analog also demonstrated potent activity in an in vitro Aedes Malpighian tubule fluid secretion assay. Similar comparisons of analog potency cannot be made to tick kinins because no endogenous kinin has yet been identified. These potent, biostable analogs represent ideal new tools for endocrinologists studying arthropod kinin regulated processes in vivo, particularly for ticks in which their role remains to be established.