Biostable agonists that match or exceed activity of native insect kinins on recombinant arthropod GPCRs

Taneja-Bageshwar, Suparna; Strey, Alison; Isaac, R. Elwyn; Coast, Geoffrey M.; Zubrzak, Paweł; Pietrantonio, Patricia V.; Nachman, Ronald J.

doi:10.1016/j.ygcen.2008.10.013

Cited by 47 publications

(62 citation statements)

References 40 publications

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“…Here, we exposed mosquitoes to sucrose solutions containing potent and biostable insect kinin analogs that are lethal to aphids and that are active on the recombinant Aedae-KR (12,26). Floral nectar, which is fed upon by diurnal mosquitoes such as A. aegypti, contains ∼55% sucrose, and both sexes prefer disaccharides, sucrose and trehalose, over monosaccharides (27).…”

Section: Discussionmentioning

confidence: 99%

“…All activate recombinant mosquito and tick kinin receptors in CHO-K1 cells, with 1728 being the most potent on the Aedae-KR (EC 50 , 76 nM), followed by 1460 (EC 50 , 367 nM) and 1729 (EC 50 , 625 nM) (12,26). Analogs 1728 and 1460 (12,26) also have potent diuretic activity in the Malpighian tubules of A. aegypti in vitro (8). Although both the Aib-containing analogs 1728 and 1729 elicit hindgut contractions in Rhodnius; 1728 is more potent (39).…”

Section: Discussionmentioning

confidence: 99%

“…Although both the Aib-containing analogs 1728 and 1729 elicit hindgut contractions in Rhodnius; 1728 is more potent (39). Structural modifications of insect kinins, such as the incorporation of Aib and β-amino acids with an additional methylene group (-CH 2 -), render these peptides biostable, because they are protease resistant (8,(10)(11)(12)26). Our hypothesis is that the potent analog 1728 enters the labellar and tarsal sensilla (30) and diffuses through the aqueous sensillum lymph to activate the Aedae-KR expressed in sucrose taste neurons, thereby decreasing sucrose taste perception.…”

Section: Discussionmentioning

confidence: 99%

“…We designed kinin analogs to be resistant to degrading peptidases and therefore exhibit sustained high potency (10,11). One biostable kinin peptidomimetic containing aminoisobutyric acid, 1728, has potency similar to or higher than the aedeskinins on recombinant receptors (12). Such biostable kinin analogs have potential in the control of insect pests because they reduce feeding in lepidopteran larvae (10,13) and increase aphid mortality (14,15).…”

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confidence: 99%

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Leucokinin mimetic elicits aversive behavior in mosquito Aedes aegypti (L.) and inhibits the sugar taste neuron

Kwon

Agha

Smith

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Insect kinins (leucokinins) are multifunctional peptides acting as neurohormones and neurotransmitters. In females of the mosquito vector Aedes aegypti (L.), aedeskinins are known to stimulate fluid secretion from the renal organs (Malpighian tubules) and hindgut contractions by activating a G protein-coupled kinin receptor designated "Aedae-KR." We used protease-resistant kinin analogs 1728, 1729, and 1460 to evaluate their effects on sucrose perception and feeding behavior. In no-choice feeding bioassays (capillary feeder and plate assays), the analog 1728, which contains α-amino isobutyric acid, inhibited females from feeding on sucrose. It further induced quick fly-away or walk-away behavior following contact with the tarsi and the mouthparts. Electrophysiological recordings from single long labellar sensilla of the proboscis demonstrated that mixing the analog 1728 at 1 mM with sucrose almost completely inhibited the detection of sucrose. Aedae-KR was immunolocalized in contact chemosensory neurons in prothoracic tarsi and in sensory neurons and accessory cells of long labellar sensilla in the distal labellum. Silencing Aedae-KR by RNAi significantly reduced gene expression and eliminated the feeding-aversion behavior resulting from contact with the analog 1728, thus directly implicating the Aedae-KR in the aversion response. To our knowledge, this is the first report that kinin analogs modulate sucrose perception in any insect. The aversion to feeding elicited by analog 1728 suggests that synthetic molecules targeting the mosquito Aedae-KR in the labellum and tarsi should be investigated for the potential to discover novel feeding deterrents of mosquito vectors.neuropeptide GPCR | sucrose taste | sensory neuron | chemical target validation | feeding deterrent

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Leucokinin mimetic elicits aversive behavior in mosquito Aedes aegypti (L.) and inhibits the sugar taste neuron

Kwon

Agha

Smith

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In insects they regulate major biological processes such as reproduction, development, locomotion as well as feeding6 and thus provide novel targets for insecticide discovery which have not yet been exploited.…”

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Disruption of aminergic signalling reveals novel compounds with distinct inhibitory effects on mosquito reproduction, locomotor function and survival

Fuchs

Rende

Crisanti

et al. 2014

Sci Rep

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Insecticide resistance amongst disease vectors is a growing problem and novel compounds are needed. Biogenic amines are important for neurotransmission and we have recently shown a potential role for these in mosquito fertility. Here, we dissected the relative contribution of different aminergic signalling pathways to biological processes essential for vectorial capacity such as fertility, locomotion and survival by injecting agonists and antagonists and showed that octopaminergic/tyraminergic signalling is essential for oviposition and hatching rate. We show that egg melanisation is regulated by adrenergic signalling, whose disruption causes premature melanisation specifically through the action of tyramine. In addition to this, co-injection of tyramine with DOPA, the precursor of melanin, had a strong cumulative negative effect on mosquito locomotion and survival. Dopaminergic and serotonergic antagonists such as amitriptyline and citalopram recapitulate this effect. Together these results reveal potential new target sites for the development of future mosquito sterilants and insecticides.

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Assessment of neuropeptide binding sites and the impact of biostable kinin and CAP2b analogue treatment on aphid (Myzus persicae and Macrosiphum rosae) stress tolerance

Alford

Marley

Dornan

et al. 2019

Pest Management Science

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BACKGROUND Neuropeptides are regulators of critical life processes in insects and, due to their high specificity, represent potential targets in the development of greener insecticidal agents. Fundamental to this drive is understanding neuroendocrine pathways that control key physiological processes in pest insects and the screening of potential analogues. The current study investigated neuropeptide binding sites of kinin and CAPA (CAPA‐1) in the aphids Myzus persicae and Macrosiphum rosae and the effect of biostable analogues on aphid fitness under conditions of desiccation, starvation and thermal (cold) stress. RESULTS M. persicae and M. rosae displayed identical patterns of neuropeptide receptor mapping along the gut, with the gut musculature representing the main target for kinin and CAPA‐1 action. While kinin receptor binding was observed in the brain and VNC of M. persicae , this was not observed in M. rosae . Furthermore, no CAPA‐1 receptor binding was observed in the brain and VNC of either species. CAP2b/PK analogues (with CAPA receptor cross‐activity) were most effective in reducing aphid fitness under conditions of desiccation and starvation stress, particularly analogues 1895 ( 2Abf ‐ Suc ‐FGPRLa) and 2129 ( 2Abf ‐ Suc ‐ A TPRIa), which expedited aphid mortality. All analogues, with the exception of 2139‐Ac, were efficient at reducing aphid survival under cold stress, although were equivalent in the strength of their effect. CONCLUSION In demonstrating the effects of analogues belonging to the CAP2b neuropeptide family and key analogue structures that reduce aphid fitness under stress conditions, this research will feed into the development of second generation analogues and ultimately the development of neuropeptidomimetic‐based insecticidal agents. © 2019 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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Biostable agonists that match or exceed activity of native insect kinins on recombinant arthropod GPCRs

Cited by 47 publications

References 40 publications

Leucokinin mimetic elicits aversive behavior in mosquito Aedes aegypti (L.) and inhibits the sugar taste neuron

Leucokinin mimetic elicits aversive behavior in mosquito Aedes aegypti (L.) and inhibits the sugar taste neuron

Disruption of aminergic signalling reveals novel compounds with distinct inhibitory effects on mosquito reproduction, locomotor function and survival

Assessment of neuropeptide binding sites and the impact of biostable kinin and CAP2b analogue treatment on aphid (Myzus persicae and Macrosiphum rosae) stress tolerance

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