|Nachman, Ronald - Ron|
Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/5/2007
Publication Date: 2/15/2008
Citation: Taneja-Bageshwar, S., Strey, A.A., Kaczmarek, K., Zabrocki, J., Pietrantonio, P., Nachman, R.J. 2008. Comparison of insect kinin analogs with cis-peptide bond, type VI-turn motifs identifies optimal stereochemistry for interaction with a recombinant arthropod kinin receptor from the southern cattle tick, Boophilus microplus. Peptides. 29:295-301. 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. Neuropeptide mimics must be designed that resist degradation by enzymes in the digestive tract and blood of pest insects and interact with the active site within agricultural or medical pests by over-activating or blocking critical, neuropeptide-regulated life functions. We report on the identification of an optimal molecular scaffold to use in the design of biostable mimics of the insect kinin neuropeptide class capable of successfully interacting with the active site of the cattle fever tick. The experiments reported within also shed light on the specific mechanism by which the neuropeptide interacts with the active site. Although the function of these neuropeptides in ticks is currently unknown, they are known to be involved in the regulation of the critical process of water balance in insects. This work represents an important milestone and lead in the development of practical neuropeptide-like substances that will effectively control arthropod pests in an environmentally friendly fashion.
Technical Abstract: The multifunctional ‘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; and are associated with the regulation of diuresis in a variety of species of insects. We previously reported the functional expression of a southern cattle tick (Boophilus microplus) G protein-coupled receptor that is activated by insect kinins. Four different stereochemical variants of each of the 4-aminopyroglutamic acid (APy) and tetrazole moieties, mimics of a cis-peptide bond, type VI '-turn in insect kinins were now evaluated on the expressed tick receptor using a calcium bioluminescence plate assay. This study represents the first investigation of the interaction of restricted-conformation analogs incorporating components that mimic specific conformations and/or peptide bond orientations in an expressed arthropod neuropeptide receptor. Analog Ac-RF[APy]WGa (2R,4S) was at least ten fold more active than the other analogs, thus identifying the optimal stereochemistry for tick receptor interaction. The optimal stereochemistry for the tetrazole insect kinin analogs in the tick receptor assay was identified as (D,L). The APy is superior to the tetrazole as a scaffold for the design of mimetic insect kinin analogs. These biostable analogs provide 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.