SYNTHETIC COMPETITIVE ANTAGONISTS OF CORTICOTROPIN-RELEASING FACTOR - EFFECT ON ACTH-SECRETION IN THE RAT
SYNTHETIC COMPETITIVE ANTAGONISTS OF CORTICOTROPIN-RELEASING FACTOR - EFFECT ON ACTH-SECRETION IN THE RAT
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DOI：
10.1126/science.6326264
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发表时间：
1984-01-01
期刊：
影响因子：
56.9
通讯作者：
VALE, W
中科院分区：
文献类型：
--
作者：
RIVIER, J;RIVIER, C;VALE, W
合成促肾上腺皮质激素释放因子（CRF）家族已知成员的多肽类似物，并在体外和体内测试其增强的效力或竞争性拮抗作用。预测方法和物理化学测量已经表明内部次级α-螺旋构象跨越CRF家族的至少3个成员的约25个残基。最大化α-通过从天然已知序列（大鼠/人和绵羊CRF，sauvagine和鲤鱼和吸盘尾加压素1）进行氨基酸取代的螺旋形成潜力导致合成了类似物，其在体外的效力是任一亲本肽的两倍以上。相反，某些氨基末端缩短的片段，如α-螺旋CRF或绵羊CRF残基8至41、9至41和10至41是体外竞争性抑制剂。选择的拮抗剂进行了检查，也是有活性的体内。
Polypeptide analogs of the known members of the corticotropin-releasing factor (CRF) family were synthesized and tested in vitro and in vivo for enhanced potency or competitive antagonism. Predictive methods and physicochemical measurements had suggested an internal secondary .alpha.-helical conformation spanning about 25 residues for at least 3 members of the CRF family. Maximization of .alpha.-helix-forming potential by amino acid substitutions from the native known sequences (rat/human and ovine CRF, sauvagine and carp and sucker urotensin 1) led to the synthesis of an analog that was more than twice as potent as either of the parent peptides in vitro. In contrast, certain amino-terminally shortened fragments, such as .alpha.-helical CRF or ovine CRF residues 8 to 41, 9 to 41 and 10 to 41, were competitive inhibitors in vitro. Selected antagonists were examined and also were active in vivo.