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首页> 外文期刊>Journal of Medicinal Chemistry >Introduction of a Chemical Constraint in a Short Peptide Derived from Human Acidic Fibroblast Growth Factor Elicits Mitogenic Structural Determinants
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Introduction of a Chemical Constraint in a Short Peptide Derived from Human Acidic Fibroblast Growth Factor Elicits Mitogenic Structural Determinants

机译:从人酸性成纤维细胞生长因子衍生的短肽中的化学约束条件引入促成丝结构决定簇。

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摘要

Fibroblast growth factors (FGFs) are regulatory proteins associated with a number of physiological and pathological states. On the basis of data suggesting a functional role for specific regions of human acidic FGF (aFGF), a linear peptide encompassing residues 99-108 (peptide1) and its cyclic analogue (peptide 2) were synthesized and their functional and structural features were investigated. While peptide 1 is inactive on Balb/c 3T3 fibroblasts, peptide 2 is mitogenic with ED_(50) of ~50 μM. Moreover, peptide 1 is not able to inhibit the binding of human aFGF to cellular receptors whereas peptide 2 exhibits significant inhibitory activity. The NMR-derived solution conformers indicated the presence, only in peptide 2, of structural elements that we believe are related to its ability to emulate the biological activity of the native protein. These results suggest that the expression of mitogenic activity in short peptides, besides the presence of specific amino acids, requires the existence of stable structural features. In addition, they indicate that the introduction of chemical restraints in peptides can provide novel possibilities for the development of receptor agonists or antagonists.
机译:成纤维细胞生长因子(FGFs)是与多种生理和病理状态相关的调节蛋白。根据表明对人酸性FGF(aFGF)特定区域起作用的数据,合成了包含残基99-108(肽1)及其环状类似物(肽2)的线性肽,并研究了它们的功能和结构特征。肽1对Balb / c 3T3成纤维细胞无活性,而肽2有丝分裂,ED_(50)约为50μM。此外,肽1不能抑制人aFGF与细胞受体的结合,而肽2则表现出明显的抑制活性。 NMR衍生的溶液构象异构体表明,仅在肽2中存在我们认为与其模拟天然蛋白质生物学活性的能力有关的结构元件。这些结果表明,除了特定氨基酸的存在以外,短肽中有丝分裂活性的表达还需要稳定的结构特征。另外,它们表明在肽中引入化学限制可以为受体激动剂或拮抗剂的开发提供新的可能性。

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