Nachman R J, Roberts V A, Holman G M, Beier R C
Food Animal Protection Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, College Station, TX 77845, USA.
Regul Pept. 1995 Jun 27;57(3):359-70. doi: 10.1016/0167-0115(95)00049-H.
Three N-terminal amino acid residues of the C-terminal core pentapeptide Phe-X-Pro-Arg-Leu-NH2 (X = Gly, Ser, Thr, Val) of the pryokinin/PBAN insect neuropeptide family were replaced by nonpeptide moieties. To reestablish some of the conformational properties lost upon removal of the peptide bonds and Pro of the three amino acid residue block, carbocyclic Pro-mimetic components were incorporated into pseudodipeptide analogs. The most active analog contained a trans-DL-1,2-cyclopentanedicarboxyl carbocyclic component and proved to be over 3 orders of magnitude more potent than a simple, straight chain pseudodipeptide analog and approached the potency of the pentapeptide core in a cockroach hindgut myotropic bioassay. The pseudodipeptide analog retains a critical carbonyl residue which can participate in a hydrogen bond that stabilizes a beta-turn conformation in the active core region of the pyrokinin/PBAN peptides. This study demonstrates that knowledge of active conformation can be used to enhance the biological potency of pseudopeptide mimetic analogs of insect neuropeptides. The analogs represent a milestone in the development of pseudopeptide and nonpeptide mimetic analogs of this peptide family, which has been associated with such critical physiological processes as hindgut and oviduct contraction, pheromone biosynthesis, diapause induction, and induction of melanization and reddish coloration in a variety of insects. Mimetic analogs are potentially valuable tools to insect neuroendocrinologists studying these physiological processes and/or engaged in the development of future pest management strategies.
将促激肽/ PBAN昆虫神经肽家族C末端核心五肽Phe-X-Pro-Arg-Leu-NH2(X = Gly、Ser、Thr、Val)的三个N末端氨基酸残基替换为非肽部分。为了重建因去除三个氨基酸残基片段的肽键和脯氨酸而丧失的一些构象性质,将碳环脯氨酸模拟成分引入假二肽类似物中。活性最高的类似物含有反式-DL-1,2-环戊烷二羧酸碳环成分,在蟑螂后肠肌动生物测定中,其效力比简单的直链假二肽类似物高3个数量级以上,接近五肽核心的效力。该假二肽类似物保留了一个关键的羰基残基,它可以参与氢键形成,从而稳定促激肽/ PBAN肽活性核心区域的β-转角构象。这项研究表明,活性构象的知识可用于提高昆虫神经肽假肽模拟类似物的生物活性。这些类似物代表了该肽家族假肽和非肽模拟类似物开发中的一个里程碑,该肽家族与诸如后肠和输卵管收缩、信息素生物合成、滞育诱导以及多种昆虫的黑化和红色化诱导等关键生理过程相关。模拟类似物对于研究这些生理过程和/或致力于未来害虫管理策略开发的昆虫神经内分泌学家来说,可能是有价值的工具。