|ABDULGANIYYU, IBRAHIM - University Of Cape Town|
|KACZMAREK, KRZYSZTOF - Technical University Of Lodz|
|ZABROCKI, JANUSZ - Technical University Of Lodz|
|VERLINDEN, HELEEN - Catholic University Of Leuven|
|SCHELLENS, SAM - Catholic University Of Leuven|
|MARCHAL, ELISABETH - Catholic University Of Leuven|
|VANDENBROECK, JOZEF - Catholic University Of Leuven|
|MARCO, HEATHER - University Of Cape Town|
|JACKSON, GRAHAM - University Of Cape Town|
Submitted to: Journal of Insect Biochemistry and Molecular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/3/2020
Publication Date: 10/15/2020
Citation: Abdulganiyyu, I.A., Kaczmarek, K., Zabrocki, J., Nachman, R.J., Verlinden, H., Schellens, S., Marchal, E., Vandenbroeck, J., Marco, H., Jackson, G.E. 2020. Conformational analysis of a cyclic AKH neuropeptide analog that elicits selective activity on locust vs honeybee receptor. Journal of Insect Biochemistry and Molecular Biology. 125:103362. https://doi.org/10.1016/j.ibmb.2020.103362.
Interpretive Summary: Because of problems with the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling insect pests. The basic premise of this research is that neuropeptides (short chains of amino acids) serve as potent hormone messengers in insects to regulate vital functions. Nevertheless, neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest and inability to penetrate the outer shell of insects. New, selective control measures may be developed by designing stable mimics of these neuropeptide hormones that interact with the active site within the agricultural pest in such a way as to either inhibit or over-stimulate critical neuropeptide-regulated life functions. In insects, AKH regulates energy utilization, locomotion and flight. The work identifies 3D characteristics required of AKH hormone mimics to interact selectively with the active site of a pest insect (the locust), while showing no activity on the active site of the beneficial honeybee. This information is critical for the design and development of practical neuropeptide-like substances that can function as environmentally friendly and effective agents for the control of pest insect populations that are safe to beneficial insects like the honeybee.
Technical Abstract: Neuropeptides belonging to the adipokinetic hormone (AKH) family elicit metabolic effects as their main function in insects, by mobilizing trehalose, diacylgycerol, or proline, which are released from the fat body into the hemolymph as energy sources for muscle contraction required for energy-intensive processes, such as locomotion. One of the AKHs produced in locusts is a decapeptide, Locmi-AKH-I (pELNFTPNWGT-NH2). A head-to-tail cyclic, octapeptide analog of Locmi-AKH-I, cycloAKH (cyclo[LNFTPNWG]) was synthesized to severely restrict the conformational freedom of the AKH structure. In vitro, cycloAKH selectively retains full efficacy and retention of potency on a pest insect (desert locust) AKH receptor, while showing little or no activation of the AKH receptor of a beneficial insect (honeybee). Molecular dynamic analysis incorporating NMR data indicate that cycloAKH preferentially adopts a type II ß-turn under micelle conditions, whereas its linear counterpart and natural AKH adopts a type VI ß-turn under similar conditions. CycloAKH, linear LNFTPNWG-NH2, and Locmi-AKH-I feature the same binding site during docking simulations with the desert locust AKH receptor (Schgr-AKHR), but differ in the details of the ligand/receptor interactions. Since the locust AKH receptor has a greater tolerance than the honeybee receptor for the cyclic conformational constraint in in vitro receptor assays, it could suggest a greater tolerance for a shift in the direction of the type II ß turn exhibited by cycloAKH from the type IV ß turn of the linear octapeptide and the native locust decapeptide AKH. Selectivity in biostable mimetic analogs could potentially be enhanced by incorporating conformational constraints that emphasize this shift. Biostable mimetic analogs of AKH offer the potential of selectively disrupting AKH-regulated processes, leading to novel, environmentally benign control strategies for pest insect populations.