Department of Chemistry, University of Cape Town, Private Bag, Rondebosch, Cape Town, 7701, South Africa.
Insect Control and Cotton Disease Research Unit, Southern Plains Agricultural Research Center, U.S. Department of Agriculture, 2881 F/B Road, College Station, TX 77845, USA; Lodz University of Technology, 90-924, Lodz, Poland.
Insect Biochem Mol Biol. 2020 Oct;125:103362. doi: 10.1016/j.ibmb.2020.103362. Epub 2020 Jul 28.
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-NH). 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 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 β-turn under micelle conditions, whereas its linear counterpart and natural AKH adopts a type VI β-turn under similar conditions. CycloAKH, linear LNFTPNWG-NH, 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. However, cycloAKH failed to enter the binding pocket of the honeybee receptor 3D model during docking simulations. Since the locust AKH receptor has a greater tolerance than the honeybee receptor for the cyclic conformational constraint in vitro receptor assays, it could suggest a greater tolerance for a shift in the direction of the type II β turn exhibited by cycloAKH from the type VI β 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.
神经肽属于激动激素 (AKH) 家族，通过动员海藻糖、二酰基甘油或脯氨酸作为能量来源，将其从脂肪体释放到血淋巴中，为肌肉收缩提供能量，这是需要能量密集型过程（如运动）的主要功能。在蝗虫中产生的一种 AKH 是一种十肽，Locmi-AKH-I (pELNFTPNWGT-NH)。Locmi-AKH-I 的头尾环八肽类似物 cycloAKH（cyclo[LNFTPNWG]）被合成，以严重限制 AKH 结构的构象自由度。在体外，cycloAKH 选择性地保留对害虫（沙漠蝗）AKH 受体的全部效力，而对有益昆虫（蜜蜂）的 AKH 受体的激活作用很小或没有。包含 NMR 数据的分子动力学分析表明，cycloAKH 在胶束条件下优先采用 II 型 β-转角，而其线性对应物和天然 AKH 在类似条件下采用 VI 型 β-转角。在与沙漠蝗 AKH 受体 (Schgr-AKHR) 的对接模拟中，cycloAKH、线性 LNFTPNWG-NH 和 Locmi-AKH-I 具有相同的结合位点，但配体/受体相互作用的细节不同。然而，在对接模拟中，cycloAKH 未能进入蜜蜂受体 3D 模型的结合口袋。由于蝗虫 AKH 受体比蜜蜂受体在体外受体测定中对环状构象约束具有更大的耐受性，因此这可能表明对环状的耐受性更大向 II 型 β 转角的方向转变，这与线性八肽和天然蝗虫十肽 AKH 的 VI 型 β 转角不同。通过引入强调这种转变的构象约束，可以提高生物稳定模拟物类似物的选择性。AKH 的生物稳定模拟物有可能选择性地破坏 AKH 调节的过程，为害虫种群提供新的、环境友好的控制策略。
