Beusen D D, Zabrocki J, Slomczynska U, Head R D, Kao J L, Marshall G R
Center for Molecular Design, Washington University, St. Louis, MO 63130, USA.
Biopolymers. 1995 Aug;36(2):181-200. doi: 10.1002/bip.360360207.
Potent, cyclic hexapeptide analogues of somatostatin are generally believed to adopt some common secondary structural features: a II' beta turn at one end of the cycle, and a type VI turn with a cis amide bond at the other. A proposed cis amide surrogate, the 1,5-disubstituted tetrazole, has been placed into a cyclic hexapeptide analog of somatostatin in order to constrain the putative cis amide bond. The final cyclization was done by either chemical or enzymatic means. The product, cyclo(Ala6-Tyr7-D-Trp8-Lys9-Val10-Phe11-psi[CN4] ), was found to have 83% of the activity of somatostatin. Solution nmr analysis in DMSO/water revealed that the backbone as well as side chain chi1 and chi2 were well ordered. Relaxation matrix methods were used to extract distance restraints from the nuclear Overhauser effect spectroscopy data set, and these were used in a systematic search of torsional space to identify structures consistent with the nmr data. Restrained minimizations of these structures using a number of different force fields produced structures having the expected beta II' turn at D-Trp8-Lys9 and a beta VIa turn in the Phe11-psi[CN4]-Ala6 portion of the molecule. The similarity of the minimized structures to those previously reported for cyclic hexapeptide analogues of somatostatin confirms the similarity of the tetrazole geometry to that of the cis amide in solution.
人们普遍认为，强效的生长抑素环六肽类似物具有一些共同的二级结构特征：环一端有一个II'型β转角，另一端有一个带有顺式酰胺键的VI型转角。为了限制假定的顺式酰胺键，已将一种提议的顺式酰胺替代物1,5-二取代四唑引入生长抑素的环六肽类似物中。最终的环化通过化学或酶促方法完成。产物环（Ala6-Tyr7-D-Trp8-Lys9-Val10-Phe11-ψ[CN4]）的活性为生长抑素的83%。在DMSO/水中的溶液核磁共振分析表明，主链以及侧链的χ1和χ2都排列有序。使用弛豫矩阵方法从核Overhauser效应光谱数据集提取距离限制，并将其用于扭转空间的系统搜索，以识别与核磁共振数据一致的结构。使用多种不同的力场对这些结构进行受限最小化，得到的结构在D-Trp8-Lys9处具有预期的βII'转角，在分子的Phe11-ψ[CN4]-Ala6部分具有βVIa转角。最小化结构与先前报道的生长抑素环六肽类似物的结构相似性证实了溶液中四唑几何形状与顺式酰胺的几何形状相似。
