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

Abstract

BACKGROUND Kinins are multifunctional neuropeptides that regulate key insect physiological processes such as diuresis, feeding, and ecdysis. However, the physiological roles of kinins in ticks are unclear. Furthermore, ticks have an expanded number of kinin paracopies in the kinin gene. Silencing the kinin receptor (KR) in females of Rhipicephalus microplus reduces reproductive fitness. 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 KR, a G protein‐coupled receptor, and identified potent peptidomimetics. Fourteen predicted R. microplus kinins (Rhimi‐K), and 11 kinin analogs containing aminoisobutyric acid (Aib) were tested. The latter incorporated tick kinin sequences and/or were modified for enhanced resistance to arthropod peptidases. A high‐throughput screen using a calcium fluorescence assay in 384‐well plates was performed. All tested kinins and Aib analogs were full agonists. The most potent kinin and two kinin analogs were equipotent. Analogs 2414 ([Aib]FS[Aib]WGa) and 2412 ([Aib]FG[Aib]WGa) were the most active with EC50 values of 0.9 and 1.1 nM, respectively, matching the EC50 of the most potent tick kinin, Rhimi‐K‐14 (QDSFNPWGa) (EC50 = 1 nM). The potent analog 2415 ([Aib]FR[Aib]WGa, EC50 = 6.8 nM) includes both Aib molecules for resistance to peptidases and a positively charged residue, 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. © 2019 Society of Chemical Industry

Identification of Neuropeptides and Their Receptors in the Ectoparasitoid, Habrobracon hebetor

“…In insects, neuropeptides and their receptors also play significant roles in controlling myriad physiological processes, including development, reproduction, feeding, homeostasis, courtship, circadian rhythm, olfaction, movement, water, and ion homeostasis, among others (Schoofs et al, 2017 ; Dickinson et al, 2019 ; Pandit et al, 2019 ). Due to their specificity and high activity at low concentrations, neuropeptides have also been investigated as potential leads for developing new environmentally-friendly pest control agents (Xiong et al, 2019 ). Importantly, many neuropeptides are capable of pleiotropic actions such as enabling them to function as neuromodulators, co-transmitters or circulating hormones, some of effects may be exerted simultaneously (Nassel et al, 2019 ).…”

De novo assembly and analysis of the transcriptome of the Dermacentor marginatus genes differentially expressed after blood-feeding and long-term starvation

“…In addition, development of eco-friendly acaricides or tick repellents is also an promising field of tick control [ 33 ]. Reports indicated that new acaricide target genes could be used to develop effective but environmentally friendly chemicals to control tick prevalence, for instance, tick kinin receptors regulate numerous tick physiological process including ecdysis and feeding [ 34 ].…”

A random small molecule library screen identifies novel antagonists of the kinin receptor from the cattle fever tick, Rhipicephalus microplus (Acari: Ixodidae)

“…In a recent study, silencing of the tick kinin receptor in R. microplus females significantly decreased reproductive fitness, lowered the percentage of egg hatching, and – interestingly – discolored the midguts, which presumably is linked to interference with heme uptake 18 . Our previous study predicted 17 tick kinins from the R. microplus kinin precursor peptide 19 ; 14 of the shorter kinins were synthesized and tested on the recombinant tick kinin receptor, and all were agonists 20 . However, peptides are expensive to mass‐produce and susceptible to enzymatic degradation 21 .…”