Kessler H, Haupt A, Schudok M, Ziegler K, Frimmer M
Institute of Organic Chemistry, Johann Wolfgang Goethe-University, Frankfurt, Federal Republic of Germany.
Int J Pept Protein Res. 1988 Sep;32(3):183-93. doi: 10.1111/j.1399-3011.1988.tb00933.x.
Cyclic hexapeptide analogues representing the modified retro sequence of the amino acid residues 7-11 of natural somatostatin are known to protect liver cells from phalloidin poisoning. To determine the influence of steric, lipophilic, and charge effects on (a) the conformation of the backbone and the aromatic side chains and (b) the biological response, the side chains of Phe2, Lys4, and Phe6 of cyclo(-D-Pro1-Phe2-Thr3-Lys(Z)4-Trp5-Phe6-), 1a, one of the most active peptides found so far, were modified by various residues. The discussion of conformationally relevant parameters proves that neither backbone conformations nor populations of aromatic side chain rotamers were altered by these substitutions. The potency of these derivatives in a cytoprotection assay varies by at most one order of magnitude (more or less active than the parent peptide 1a). A qualitative evaluation of lipophilic, steric, and charge effects reveals the dominance of lipophilic effects of aromatic residues; the most potent compounds contain aromatic substructures in the side chain of Lys4.
已知代表天然生长抑素氨基酸残基7 - 11修饰反向序列的环状六肽类似物可保护肝细胞免受鬼笔环肽中毒。为了确定空间、亲脂性和电荷效应对（a）主链和芳香族侧链的构象以及（b）生物反应的影响，对迄今为止发现的活性最高的肽之一环（-D-脯氨酸1-苯丙氨酸2-苏氨酸3-赖氨酸（Z）4-色氨酸5-苯丙氨酸6-）（1a）的苯丙氨酸2、赖氨酸4和苯丙氨酸6的侧链进行了各种残基修饰。对构象相关参数的讨论证明，这些取代既未改变主链构象，也未改变芳香族侧链旋转异构体的数量。这些衍生物在细胞保护试验中的效力最多相差一个数量级（比母体肽1a或多或少更具活性）。对亲脂性、空间和电荷效应的定性评估揭示了芳香族残基亲脂性效应的主导地位；最有效的化合物在赖氨酸4的侧链中含有芳香族亚结构。
