Amodeo P, Naider F, Picone D, Tancredi T, Temussi P A
Istituto Chimica Molecole di Interesse Biologico (associated to the Italian National Institute for the Chemistry of Biological Systems), CNR, Arco Felice, Italy.
J Pept Sci. 1998 Jun;4(4):253-65. doi: 10.1002/(SICI)1099-1387(199806)4:4%3C253::AID-PSC142%3E3.0.CO;2-P.
Conformational studies of enkephalins are hampered by their high flexibility which leads to mixtures of quasi-isoenergetic conformers in solution and makes NOEs very difficult to detect in NMR spectra. In order to improve the quality of the NMR data, Leu-enkephalin was synthesized with 15N-labelled uniformly on all amide nitrogens and examined in a viscous solvent medium at low temperature. HMQC NOESY spectra of the labelled Leu-enkephalin in a DMSOd6/H2O) mixture at 275 K do show numerous NOEs, but these are not consistent with a single conformer and are only sufficient to describe the conformational state as a mixture of several conformers. Here a different approach to the structure-activity relationships of enkephalins is presented: it is possible to analyse the NMR data in terms of limiting canonical structures (i.e. beta- and gamma-turns) and finally to select only those consistent with the requirements of delta selective agonists and antagonists. This strategy results in the prediction of a family of conformers that may be useful in the design of new delta selective opioid peptides.
脑啡肽的构象研究受到其高度灵活性的阻碍，这种灵活性导致溶液中准等能构象异构体混合，使得核磁共振谱中很难检测到核Overhauser效应（NOEs）。为了提高核磁共振数据的质量，合成了所有酰胺氮均被15N均匀标记的亮氨酸脑啡肽，并在低温下的粘性溶剂介质中进行检测。在275 K下，标记的亮氨酸脑啡肽在二甲基亚砜-d6/水混合物中的异核多量子相干（HMQC）核Overhauser效应光谱确实显示出大量的核Overhauser效应，但这些效应与单一构象异构体不一致，仅足以将构象状态描述为几种构象异构体的混合物。本文提出了一种研究脑啡肽构效关系的不同方法：可以根据极限规范结构（即β-转角和γ-转角）分析核磁共振数据，并最终只选择那些符合δ选择性激动剂和拮抗剂要求的结构。这种策略导致预测出一类构象异构体，它们可能有助于设计新的δ选择性阿片肽。
