Synthesis and bioactivity studies of two isosteric acyclic analogues of melanin concentrating hormone.
Synthesis and bioactivity studies of two isosteric acyclic analogues of melanin concentrating hormone.
复制标题
黑色素浓缩激素的两种等排无环类似物的合成和生物活性研究。
DOI：
10.1016/0024-3205(92)90241-g
复制
发表时间：
1992
期刊：
影响因子：
6.1
通讯作者：
Hadley,ME
中科院分区：
文献类型：
--
作者：
Matsunaga,TO;Hruby,VJ;Lebl,M;Castrucci,AM;Hadley,ME
鲑鱼黑色素浓缩激素（MCH）是一种环状十七肽。MCH刺激黑素体在硬骨鱼的外皮黑素细胞内的核周聚集，导致皮肤变白。MCH含有形成10-残基环的二硫键（H-Asp-Thr-Met-Arg-Cys s-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys s-Trp-Glu-Val-OH）。有人提出，环是维持效力所必需的。为了测试这个建议，我们已经合成了两个假电子等排的类似物的MCH，不能环化。它们仅在位置5和14的侧链基团的极性上不同。其中一个肽的Cys 5和Cys 14被丝氨酸取代，另一个肽的两个位置被L α-氨基丁酸（Abu）取代。使用鱼皮生物测定，我们确定这些类似物表现出小于1/10，000的天然激素的效力。这些结果表明，二硫桥是必要的，以保持正确的构象和地形特征的激素受体结合和跨膜信号转导。
Salmon melanin concentrating hormone (MCH) is a cyclic heptadecapeptide. MCH stimulates perinuclear aggregation of melanosomes within integumental melanocytes of teleost fishes resulting in skin blanching. MCH contains a disulfide bridge forming a 10-residue ring (H-Asp-Thr-Met-Arg-Cys s-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cy s-Trp-Glu-Val-OH). It has been proposed that the ring is necessary for maintenance of potency. In order to test this proposal, we have synthesized two pseudo-isosteric analogues of MCH that cannot cyclize. They differed only in the polarity of the side chain group of positions 5 and 14. Serine was substituted for Cys 5 and Cys 14 in one peptide and L α-aminobutyrate (Abu) was the substitution at the two positions in the other peptide. Using a fish skin bioassay we determined that these analogues exhibit less than 1/10,000 th the potency of the native hormone. These results suggest that the disulfide bridge is necessary to maintain the correct conformational and topographical features of the hormone for receptor binding and transmembrane signal transduction.