Evaluation of Aib and PEG-polymer insect kinin analogs on mosquito and tick GPCRs identifies potent new pest management tools with potentially enhanced biostability and bioavailability

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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

Section: Resultssupporting

confidence: 80%

Section: Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Xiong

Kaczmarek

Zabrocki

et al. 2020

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Synthesis, aphicidal activity and conformation of novel insect kinin analogues as potential eco‐friendly insecticides

Zhang

Ling

et al. 2020

BACKGROUND The discovery of ecofriendly insecticides through a new strategy for aphid control is important because of the substantial resistance and unexpected eco‐toxicity to honeybees caused by traditional insecticides. The insect kinins, a class of multifunctional insect neuropeptides, are considered for potential application in pest control. In our previous work we developed several series of insect kinin analogues and found a promising lead II‐1 with good aphicidal activity. To seek further eco‐friendly aphicides, the optimization of II‐1 is carried out in this study. RESULTS Fifteen novel Yaa3 modified analogues based on the lead II‐1 were synthesized. The aphicidal tests indicated that IV‐3, IV‐5 and IV‐10 exhibited significant activity against the soybean aphid Aphis glycines with LC50 values of 0.0029, 0.0072 and 0.0086 mmol L–1, respectively, higher than that of lead II‐1 and the commercial Pymetrozine. The molecular modeling results showed that analogues II‐1, IV‐3, IV‐5, IV‐7 and IV‐10 formed a β‐turn‐like conformation, while the conformation of analogues IV‐1, IV‐2 and IV‐9 seemed to be linear. Some structural elements favorable for the activity were proposed based on the conformation‐activity relationship of the analogues. CONCLUSION Insect kinin analogues derived from lead II‐1 by modifying the hydrolysis site Yaa3 with natural, sterically hindered α‐ and β‐amino acids showed great potential as eco‐friendly insecticides. Inspiringly, the most active analogue IV‐3 can be a candidate for further development. The β‐turn‐like conformation and the orientation of the aromatic rings of the side chain of Phe2 and Trp4 may be critical factors beneficial to activity. © 2019 Society of Chemical Industry

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

Xiong

Baker

Pietrantonio

2021

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BACKGROUND The southern cattle tick, Rhipicephalus microplus, is a primary vector of the deadly bovine disease babesiosis. Worldwide populations of ticks have developed resistance to acaricides, underscoring the need for novel target discovery for tick control. The arthropod‐specific R. microplus kinin receptor is such a target, previously validated by silencing, which resulted in female reproductive fitness costs, including a reduced percentage of eggs hatching. RESULTS In order to identify potent small molecules that bind and activate or inhibit the kinin receptor, a high‐throughput screening (HTS) assay was developed using a CHO‐K1 cell line expressing the recombinant tick kinin receptor (BMLK3). A total of ~20 000 molecules from a random in‐house small molecule library were screened in a ‘dual‐addition’ calcium fluorescence assay. This was followed by dose–response validation of the hit molecules identified both from HTS and an in silico screen of ~390 000 molecules. We validated 29 antagonists, 11 of them were full antagonists with IC50 values between 0.67 and 8 μmol L–1. To explore the structure–activity relationships (SAR) of the small molecules, we tested the activities of seven analogs of the most potent identified antagonist, additionally discovering three full antagonists and four partial antagonists. These three potent antagonists (IC50 < 3.2 μmol L–1) were validated in vitro using the recombinant mosquito kinin receptor and showed similar antagonistic activities. In vivo, these three compounds also inhibited the mosquito hindgut contraction rate induced by a myotropic kinin agonist analog 1728. CONCLUSION Antagonists identified in this study could become pesticide leads and are reagents for probing the kinin signaling system. © 2021 Society of Chemical Industry