|XIONG, CAIXING - Texas A&M University|
|KACZMAREK, KRZYSZTOF - Technical University Of Lodz|
|ZABROCKI, JANUSZ - Technical University Of Lodz|
|PIETRANTONIO, PATRICIA - Texas A&M University|
Submitted to: General and Comparative Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2018
Publication Date: 5/15/2019
Citation: Xiong, C., Kaczmarek, K., Zabrocki, J., Pietrantonio, P.V., Nachman, R.J. 2019. 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. General and Comparative Endocrinology. 278:58-67. https://doi.org/10.1016/j.ygcen.2018.08.002.
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 mosquitoes that spread Zika, dengue and yellow fever in humans. We report here the design and evaluation on mosquito and tick ‘active sites’ of new and highly potent mimics of ‘insect kinins’ that feature enhanced resistance to inactivation and an enhanced ability to cross the outer shell of these serious pests. These discoveries add potent new tools to the tool box of endocrinologists studying how these regulatory agents work and how they might be employed to control their populations. The study will aid in the design of neuropeptide-like compounds capable of disrupting the survival of mosquitoes and ticks that spread disease in man and animals and lead to the development of novel control strategies.
Technical Abstract: Insect kinins modulate aspects of diuresis, digestion, development, and sugar taste perception through chemosensory neurons in tarsi and labellar sensilla in mosquitoes. They are, however, subject to rapid biological degradation by endogenous invertebrate peptidases. A series of a-aminoisobutyric (Aib) acid-containing insect kinin analogs incorporating sequences native to the Aedes aegypti mosquito aedeskinins were evaluated on two recombinant kinin invertebrate receptors stably expressed in cell lines, discovering a number of highly potent and biostable insect kinin mimics. On the Ae. aegypti mosquito kinin receptor, three highly potent, biostable Aib analogs matched the activity of biostable insect kinin analog 1728, that in in vivo assays previously showed disruptive and/or aversive activity in aphid, mosquito and kissing bug. These three analogs are IK-Aib-19 ([Aib]FY[Aib]WGa, EC50 = 18 nM), IK-Aib-12 (pQKFY[Aib]WGa, EC50 = 23 nM) and IK-Aib-20 ([Aib]FH[Aib]WGa, EC50 = 28 nM). On the Rhipicephalus (Boophilus) microplus tick receptor, IK-Aib-20 ([Aib]FH[Aib]WGa, EC50 = 2 nM) is more potent than 1728 by a factor of 3. Seven other biostable analogs exhibited an EC50 range of 5-10 nM, all of which statistically match the potency of 1728. Among the multi-Aib hexapeptide kinin analogs tested the tick receptor has a preference for the positively-charged, aromatic H over the aromatic residues Y and F in the X1 variable position ([Aib]FX1[Aib]WGa), whereas the mosquito receptor does not distinguish between them. In contrast, in a mono-Aib pentapeptide analog framework (FX1[Aib]WGa), both receptors exhibit a preference for Y over H in the variable position. Among analogs incorporating polyethylene glycol (PEG) polymer attachments at the N-terminus that can confer enhanced bioavailability and biostability, three matched or surpassed the potency of a positive control peptide. On the tick receptor IK-PEG-9 (P8-R[Aib]FF[Aib]WGa) was the most potent. Two others, IK-PEG-8 (P8-RFFPWGa) and IK-PEG-6 (P4-RFFPWGa), were most potent on the mosquito receptor, with the first surpassing the activity of the positive control peptide. These analogs and others in the IK-Aib series expand the toolbox of potent, biostable and bioavailable tools accessible to invertebrate endocrinologists studying the structural requirements for aversive behavior in mosquitoes, inhibition of blood feeding in Rhodnius prolixus, and the as yet unknown role of the insect kinins in ticks. They may contribute to the development of selective, environmentally friendly pest arthropod control agents.