A potent cyclic hexapeptide analogue of somatostatin
A potent cyclic hexapeptide analogue of somatostatin
复制标题
生长抑素的有效环状六肽类似物
作者：
D. Veber;R. Freidinger;D. Perlow;W. J. Paleveda;F. W. Holly;R. Strachan;R. Nutt;B. Arison;C. Homnick;W. Randall;M. Glitzer;R. Saperstein;R. Hirschmann
构象分析导致生长抑素类似物的设计和合成，其作用持续时间延长1-3。引入共价构象限制并消除不需要的氨基酸导致合成高活性双环类似物 I，环（Aha-Cys-Phe-D-Trp-Lys-Thr-Cys）2,3，其在体外和体内抑制生长激素释放以及体内胰高血糖素和胰岛素释放方面表现出等于或大于生长抑素的效力（Aha， 7-氨基庚酸）。这些结果表明，该类似物的氨基酸-Phe-D-Trp-Lys-Thr-和相应的生长抑素残基7-10含有表达上述生物活性所需的所有元件，并且片段-Cys-Aha-Ctys-作为构象约束，使四肽获得生物活性构象。结论是，这种限制还导致观察到对胰蛋白酶等肽酶代谢的敏感性降低，并且允许长时间的作用和口服活性2,3。如果-Cys-Aha-Cys-序列的唯一目的确实只是构象约束，那么应该可以设计替代的、更简单的约束部分。我们使用计算机建模和图形系统4来检查可能的替代分子片段，并在此报告了生长抑素的高活性环状六肽类似物的合成。
Conformational analysis has resulted in the design and synthesis of somatostatin analogues which show increased duration of action1–3. The introduction of covalent conformational constraints and elimination of amino acids that are not required led to the synthesis of the highly active bicyclic analogue I, cyclo(Aha-Cys-Phe-D-Trp-Lys-Thr-Cys)2,3, which showed potency equal to or greater than that of somatostatin for the inhibition of growth hormone release in vitro and in vivo, as well as for the inhibition of glucagon and insulin release in vivo (Aha, 7-aminoheptanoic acid). These results suggested that the amino acids -Phe-D-Trp-Lys-Thr- of this analogue and the corresponding residues 7–10 of somatostatin contain all the elements necessary for the expression of the above biological activities, and that the fragment -Cys-Aha-Ctys- serves as a conformational constraint, allowing the tetrapeptide to attain a bioactive conformation. It was concluded that such constraint also results in the observed reduced susceptibility to metabolism by peptidases such as trypsin and has permitted both a long duration of action and oral activity2,3. If the sole purpose of the -Cys-Aha-Cys- sequence is indeed only conformational constraint, then it should be possible to design alternative, simpler constraining moieties. We have used a computer modelling and graphics system4 to examine possible alternative molecular fragments and report here the synthesis of a highly active cyclic hexapeptide analogue of somatostatin.