Sheh L, Mokotoff M, Abraham D J
Int J Pept Protein Res. 1987 Apr;29(4):509-20. doi: 10.1111/j.1399-3011.1987.tb02278.x.
As part of our continuing search for new agents which might be useful for the treatment of sickle-cell anemia, we have synthesized two cyclic tetrapeptide homologs, cyclo(-Val-Glu[-Thr-Pro-]-OH) (1a) and cyclo(-Phe-Glu[-Thr-Pro-]-OH (1b), and a tetrapeptide lactone homolog cyclo(H-Thr-Pro-Val-Glu-OH) (2). The intent was that these peptides would mimic a tetrapeptide region around the mutation site of HbS and thus be able to bind at the acceptor site of HbS and thereby inhibit polymerization. The synthesis of the linear peptides was accomplished in solution using both the polymeric reagent (PHBT) and DCC/HOBT methods; cyclization was accomplished by an improved method. 13C-n.m.r. studies were performed which allowed us to assign the conformation about the Thr-Pro bond in 1a and 2 as trans. The cyclic peptides were tested for their ability to increase the solubility of HbS under deoxygenating conditions, but only 1a had any antigelling activity, albeit low.
作为我们持续寻找可能用于治疗镰状细胞贫血的新药物的一部分，我们合成了两种环四肽类似物，环（-缬氨酸-谷氨酸[-苏氨酸-脯氨酸-]-OH）（1a）和环（-苯丙氨酸-谷氨酸[-苏氨酸-脯氨酸-]-OH）（1b），以及一种四肽内酯类似物环（H-苏氨酸-脯氨酸-缬氨酸-谷氨酸-OH）（2）。目的是这些肽将模拟HbS突变位点周围的四肽区域，从而能够在HbS的受体位点结合，进而抑制聚合。线性肽的合成在溶液中使用聚合物试剂（PHBT）和DCC/HOBT方法完成；环化通过改进的方法完成。进行了13C核磁共振研究，使我们能够确定1a和2中苏氨酸-脯氨酸键的构象为反式。测试了环肽在脱氧条件下增加HbS溶解度的能力，但只有1a具有任何抗凝胶化活性，尽管活性较低。
