Lamthanh H, Bdolah A, Creminon C, Grassi J, Menez A, Wollberg Z, Kochva E
Departement d'Ingenierie, Etudes des Proteines, DSV, CEA, CE, Gif sur Yvette, France.
Toxicon. 1994 Sep;32(9):1105-14. doi: 10.1016/0041-0101(94)90394-8.
The 21 amino acid sarafotoxins (SRTX) c and d/e as well as endothelin-3 (ET-3) are known to be less toxic and weaker pharmacologically than the other isopeptides SRTX-a, SRTX-b and ET-1. Since SRTX-c, SRTX-d/e and ET-3 possess a Thr instead of a Ser at position 2, we investigated the possibility that this mutation could be responsible for the observed biological differences. Here we show that the synthetic [Thr2]SRTX-b has indeed a lower vasoconstriction efficacy (approximately 35%) in the rabbit aorta, but it is nearly as potent as SRTX-b in toxicity tests and in influencing contraction of the rat uterus. Using monoclonal antibodies directed against the structurally related endothelin-1, we also show that the antigenicity of the analogue is comparable to that of SRTX-b, suggesting that the overall structure of the two peptides is similar, despite the substitution at position 2. We suggest that the Thr2 substitution contributes to the lower activity of the 'weak' peptides in some systems; however, additional substitutions found in the 'weak' peptides of the ET/SRTX family most probably contribute to their low pharmacological activity.
已知21个氨基酸的沙罗毒素（SRTX）c和d/e以及内皮素-3（ET-3）在毒性和药理活性方面比其他异肽SRTX-a、SRTX-b和ET-1更低。由于SRTX-c、SRTX-d/e和ET-3在第2位含有苏氨酸而非丝氨酸，我们研究了这种突变是否可能是观察到的生物学差异的原因。在此我们表明，合成的[Thr2]SRTX-b在兔主动脉中的血管收缩效力确实较低（约35%），但在毒性试验和影响大鼠子宫收缩方面，其效力与SRTX-b几乎相同。使用针对结构相关的内皮素-1的单克隆抗体，我们还表明该类似物的抗原性与SRTX-b相当，这表明尽管在第2位有取代，但这两种肽的整体结构相似。我们认为Thr2取代导致了“弱”肽在某些系统中的活性较低；然而，ET/SRTX家族“弱”肽中发现的其他取代很可能导致了它们较低的药理活性。
