Chakravarty S, Connolly M, Kyle D J
Scios Nova, Baltimore, MD, USA.
Pept Res. 1995 Jan-Feb;8(1):16-9.
We recently proposed a model of bradykinin bound to the rat bradykinin B2 receptor that is constructed on the basis of structural homology modeling to the criomicroscopic structure of the seven transmembrane domains of bacteriorhodopsin, extensive conformational searches and experimental mutagenesis results. On the basis of that model, a novel third-generation pseudopeptide antagonist, NPC 18325 (D-Arg1-Arg2-[aminotridecanoyl]3-Ser4-D-Tic5-Oic6++ +-Arg7) (Ki = 440 nM, guinea pig ileum), was designed and also reported. NPC 18325 has been proposed to adopt a C-terminal beta turn separated from N-terminal positive charges by a linear 12 carbon chain spacer. Experimentally, the four amino acids making up the C-terminus have been shown by NMR to preferentially adopt a beta turn at neutral pH in aqueous solution. We now present a series of peptides, related to and including NPC 18325, that explore the relationship between the length of the carbon chain and the affinity to the human bradykinin B2 receptor. The results show that there is a structure-activity relationship (SAR) associated with the chain length and that these pseudopeptides have better affinity to the human bradykinin receptor than they have to the guinea pig ileal-derived B2 receptor. Specifically, peptide I (a 12-methylene linker) had a measured Ki of 31 nM and peptide V (a 4-methylene linker) had a Ki of 471 nM. Implications regarding conformation and hydrophobicity are also described.
我们最近提出了一种结合大鼠缓激肽B2受体的缓激肽模型，该模型是基于与细菌视紫红质七个跨膜结构域的低温显微镜结构的结构同源性建模、广泛的构象搜索和实验诱变结果构建的。基于该模型，设计并报道了一种新型第三代假肽拮抗剂NPC 18325（D-Arg1-Arg2-[氨基十三烷酰基]3-Ser4-D-Tic5-Oic6+++-Arg7）（Ki = 440 nM，豚鼠回肠）。有人提出NPC 18325会形成一个C端β转角，通过一个线性的12碳链间隔基与N端正电荷隔开。实验表明，构成C端的四个氨基酸在中性pH的水溶液中通过核磁共振显示优先采用β转角结构。我们现在展示了一系列与NPC 18325相关并包括NPC 18325的肽，以探索碳链长度与对人缓激肽B2受体亲和力之间的关系。结果表明，存在与链长相关的构效关系（SAR），并且这些假肽对人缓激肽受体的亲和力比对豚鼠回肠来源的B2受体的亲和力更好。具体而言，肽I（一个12-亚甲基连接体）测得的Ki为31 nM，肽V（一个4-亚甲基连接体）的Ki为471 nM。还描述了有关构象和疏水性的影响。
