Activity of native tick kinins and peptidomimetics on the cognate target G protein-coupled receptor from the cattle fever tick, Rhipicephalus microplus (Acari, Ixodidae)

Authors: XIONG, CAIXING - Texas A&M University; KACZMAREK, KRZYSZTOF - Technical University Of Lodz; ZABROCKI, JANUSZ - Technical University Of Lodz; Nachman, Ronald; PIETRANTONIO, PATRICIA - Texas A&M University

Submitted to: Pest Management Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/28/2019
Publication Date: 9/10/2020
Publication URL: https://handle.nal.usda.gov/10113/7105664
Citation: Xiong, C., Kaczmarek, K., Zabrocki, J., Nachman, R.J., Pietrantonio, P. 2020. Activity of native tick kinins and peptidomimetics on the cognate target G protein-coupled receptor from the cattle fever tick, Rhipicephalus microplus (Acari, Ixodidae). Pest Management Science. 76:3423-3431. https://doi.org/10.1002/ps.5704.
DOI: https://doi.org/10.1002/ps.5704

Interpretive Summary: Insect pests have developed resistance to several conventional pesticides, and new approaches are needed for pest management. Although neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, the neuropeptides hold little promise as pest control agents because they can be degraded in the target pest. New, selective control agents may be developed by designing mimics of these neuropeptides that resist degradation and either inhibit or over-stimulate critical neuropeptide-regulated life functions. Neuropeptides of the ‘insect kinin’ class regulate water balance, digestion and taste sensation in insects and ticks that spread disease in livestock and humans. We report here the design and evaluation of new and highly potent mimics of ‘insect kinins’ that feature enhanced resistance to degradation and an enhanced ability to penetrate the outer shell of insects and ticks. These discoveries add potent new tools to the toolbox of scientists studying how these regulatory agents work and how they might be employed to control pest populations. Ultimately, the study will aid in the design of neuropeptide-like compounds capable of disrupting the survival of ticks that spread disease in man and animals, and lead to the development of novel control strategies.

Technical Abstract: BACKGROUND: Kinins are multifunctional neuropeptides that regulate key insect physiological processes such as diuresis, feeding, and ecdysis. However, the physiological role of kinins in ticks is unclear. Silencing the kinin-receptor in females of R. microplus reduces reproductive fitness. Further, ticks have an expanded number of kinin paracopies in the kinin gene. Thus, it appears the kinin signaling system is important for tick physiology, and its disruption may have potential for tick control. RESULTS: We determined the activities of endogenous kinins on the potential target, the kinin G protein-coupled receptor, and identified potent peptidomimetics. Fourteen predicted tick kinins of R. microplus, and eleven kinin analogs containing aminoisobutyric acid (Aib) were tested. The latter either incorporated tick native sequences or were modified for enhanced resistance to arthropod peptidases. A high-throughput cellular screen using a calcium fluorescence assay in 384-well-plates was performed. All tested kinins and Aib-analogs had full agonistic activity. The most potent groups of both kinins and analogs were equipotent. The most potent tick kinin Rmkinin14, QDSFNPWGa, had an EC50 of 1 nM. Analogs 2414 [Aib]FS[Aib]WGa and 2412 ([Aib]FG[Aib]WGa) were the most active with EC50 values (0.95 nM and 1.1 nM, respectively), matching the EC50 of the most potent tick kinin. The potent analog 2415 ([Aib]FR[Aib]WGa, EC50=7 nM) included Aib molecules for resistance to enzymatic degradation, and a positively charged residue, Arg (R), for enhanced water solubility and amphiphilic character. CONCLUSION: These tick kinins and pseudopeptides expand the repertoire of reagents for tick physiology and toxicology towards finding novel targets for tick management. Please send this to Office Assistant or PSA for ARIS input. Please let them know when the paper has been submitted, accepted, published