Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat
Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat
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DOI：
10.1124/mol.55.2.332
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发表时间：
1999-02-01
影响因子：
3.6
通讯作者：
Bouck, NP
中科院分区：
文献类型：
--
作者：
Dawson, DW;Volpert, OV;Bouck, NP
Mal II是一种19个残基的肽，来源于抗血管生成蛋白血小板反应蛋白-1（TSP-1）的第二个1型备解素样重复序列，在血管生成试验中无活性。然而，三个L-氨基酸中的任何一个被它们的D-对映体取代，赋予该肽接近完整的450-kDa TSP-1的有效的抗血管生成活性。取代的肽抑制毛细血管内皮细胞的迁移，对于D-Ile-15取代，ED 50为8.5 nM，对于D-Ser-4取代，ED 50为10 nM，对于D-Ser-5取代，ED 50为0.75 nM。在位置15处具有D-Ile的肽可以缩短至其最后7个氨基酸而几乎没有活性损失。与完整TSP-1一样，Mal II D-Ile衍生物抑制广泛的血管生成诱导剂，对内皮细胞具有选择性，并且需要CD 36受体结合才能发挥活性。多种末端修饰进一步改善肽效力。一个乙基酰胺封端的七肽也有全身活性，当腹腔注射时，它使小鼠不能建立角膜血管生成反应，这表明这种肽作为抗血管生成治疗的潜在用途。
Mal II, a 19-residue peptide derived from the second type 1 properdin-like repeat of the antiangiogenic protein thrombospondin-1 (TSP-1), was inactive in angiogenesis assays. Yet the substitution of any one of three L-amino acids by their D-enantiomers conferred on this peptide a potent antiangiogenic activity approaching that of the intact 450-kDa TSP-1. Substituted peptides inhibited the migration of capillary endothelial cells with an ED50 of 8.5 nM for the D-Ile-15 substitution, 10 nM for the D-Ser-4 substitution, and 0.75 nM for the D-Ser-5 substitution. A peptide with D-Ile at position 15 could be shortened to its last seven amino acids with little loss in activity. Like whole TSP-1, the Mal II D-Ile derivative inhibited a broad range of angiogenic inducers, was selective for endothelial cells, and required CD36 receptor binding for activity. A variety of end modifications further improved peptide potency. An ethylamide-capped heptapeptide was also active systemically in that when injected i.p. it rendered mice unable to mount a corneal angiogenic response, suggesting the potential usefulness of such peptides as antiangiogenic therapeutics.