Antiproliferative and antitumor activities of D-reverse peptides derived from the second type-1 repeat of thrombospondin-1.
Antiproliferative and antitumor activities of D-reverse peptides derived from the second type-1 repeat of thrombospondin-1.
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源自血小板反应蛋白-1 的第二个 1 型重复序列的 D-反向肽具有抗增殖和抗肿瘤活性。
DOI：
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
D. Roberts
中科院分区：
文献类型：
--
作者：
N. Guo;H. Krutzsch;J. Inman;C. Shannon;D. Roberts
细胞外基质糖蛋白血小板反应蛋白-1 (TSP1) 抑制血管生成、内皮细胞生长、运动和粘附。 TSP1 I 型重复序列的肽模拟完整蛋白的粘附和生长抑制活性，并与肝素和转化生长因子-β (TGF beta) 发生特异性相互作用。为了确定这些肽的抗血管生成活性的结构基础，我们制备了 TSP1 肽 KRFKQDGGWSHWSPWSSC 的类似物。 L-正向、L-反向和D-反向（逆向-反向）类似物显示出相同的肝素结合活性，表明肝素结合缺乏立体特异性。然而，L-反向和D-反向肽激活潜在TGFβ的能力有所降低。通过C端硫醚将正向肽和通过N端硫醚将反向肽与聚蔗糖缀合，消除了肽的粘附活性，并增强了它们对成纤维细胞生长因子2刺激的内皮细胞和乳腺癌细胞的抗增殖活性。它们的抗增殖活性与潜在的 TGF β 激活无关，因为用 Ala 残基替代 TSP1 1 型重复肽中必需的 Phe 残基增加了它们抑制 TSP1 与肝素结合和抑制内皮细胞增殖的效力。尽管缀合肽在体内无活性，但天然 TSP 肽的未缀合逆向类似物在小鼠异种移植模型中抑制乳腺肿瘤生长。因此，这些 TSP 衍生肽类似物通过其肝素结合活性而不是通过激活潜在的 TGF β 或增加细胞粘附来拮抗内皮生长。因此，这些稳定的类似物可用作成纤维细胞生长因子-2刺激的血管生成的治疗抑制剂。
The extracellular matrix glycoprotein thrombospondin-1 (TSP1) inhibits angiogenesis, endothelial cell growth, motility and adhesion. Peptides from the type I repeats of TSP1 mimic the adhesive and growth inhibitory activities of the intact protein and specifically interact with heparin and transforming growth factor-beta (TGF beta). To define the structural basis for the antiangiogenic activities of these peptides, we prepared analogs of the TSP1 peptide KRFKQDGGWSHWSPWSSC. L-forward, L-reverse, and D-reverse (retro-inverso) analogs displayed identical activities for binding to heparin, demonstrating a lack of stereospecificity for heparin binding. The L-reverse and D-reverse peptides, however, had somewhat decreased abilities to activate latent TGF beta. Conjugation of the forward peptides through a C-terminal thioether and the reverse peptides through an N-terminal thioether to polysucrose abolished the adhesive activity of the peptides and enhanced their antiproliferative activities for endothelial and breast carcinoma cells stimulated by fibroblast growth factor-2. Their antiproliferative activities were independent of latent TGF beta activation, because substitution of an Ala residue for the essential Phe residue in the TSP1 type-1 repeat peptide increased their potency for inhibiting TSP1 binding to heparin and for inhibiting endothelial cell proliferation. Although the conjugated peptides were inactive in vivo, an unconjugated retro-inverso analog of the native TSP peptide inhibited breast tumor growth in a mouse xenograft model. Thus, these TSP-derived peptide analogs antagonize endothelial growth through their heparin-binding activity rather than through activation of latent TGF beta or increasing cell adhesion. These stable analogs may therefore be useful as therapeutic inhibitors of angiogenesis stimulated by fibroblast growth factor-2.
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合成的层粘连蛋白样肽和伪肽作为潜在的抗转移剂。
影响因子：
7.3
作者：
Zhao,M;Kleinman,HK;Mokotoff,M
通讯作者：
Mokotoff,M
影响因子：
158.5
作者：
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FOLKMAN, J
DOI：
10.1073/pnas.88.11.5026
发表时间：
1991-06-01
影响因子：
11.1
作者：
IRUELAARISPE, ML;BORNSTEIN, P;SAGE, H
通讯作者：
SAGE, H
影响因子：
56.9
作者：
DAMERON, KM;VOLPERT, OV;BOUCK, N
通讯作者：
BOUCK, N
DOI：
10.1073/pnas.87.17.6624
发表时间：
1990-09-01
影响因子：
11.1
作者：
GOOD, DJ;POLVERINI, PJ;BOUCK, NP
通讯作者：
BOUCK, NP