Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23, Uppsala, Sweden.
Org Biomol Chem. 2011 Jun 7;9(11):4306-14. doi: 10.1039/c0ob00966k. Epub 2011 Apr 13.
The cyclotides are a family of circular and knotted proteins of natural origin with extreme enzymatic and thermal stability. They have a wide range of biological activities that make them promising tools for pharmaceutical and crop-protection applications. The cyclotides are divided into two subfamilies depending on the presence (Möbius) or absence (bracelet) of a cis-Pro peptide bond. In the current work we report a series of experiments to give further insight into the structure-activity relationship of cyclotides in general, and the differences between subfamilies and the role of their hydrophobic surface in particular. Selective chemical modifications of Glu, Arg, Lys and Trp residues was tested for cytotoxic activity: derivatives in which the Trp residue was modified showed low effect, demonstrating the existence of a connection between hydrophobicity and activity. However, over the full set of cyclotides examined, there was no strong correlation between the cytotoxic activity and their hydrophobicity. Instead, it seems more like that the distribution of charged and hydrophobic residues determines the ultimate degree of potency. Furthermore, we found that while the Glu residue is very important in maintaining the activity of the bracelet cyclotide cycloviolacin O2, it is much less important in the Möbius cyclotides. Despite these differences between cyclotide subfamilies, a systematic test of mixtures of cyclotides revealed that they act in an additive way.
环肽是一类具有极端酶和热稳定性的天然来源的环形和纽结蛋白家族。它们具有广泛的生物活性，使它们成为药物和作物保护应用的有前途的工具。环肽根据顺式-Pro 肽键的存在（Möbius）或不存在（手链）分为两个亚家族。在目前的工作中，我们报告了一系列实验，以进一步深入了解环肽的结构-活性关系，特别是亚家族之间的差异以及它们的疏水面在其中的作用。我们测试了 Glu、Arg、Lys 和 Trp 残基的选择性化学修饰对细胞毒性的影响：修饰 Trp 残基的衍生物显示出低效应，表明疏水性和活性之间存在联系。然而，在所检查的整套环肽中，细胞毒性与其疏水性之间没有很强的相关性。相反，似乎更像是带电和疏水性残基的分布决定了最终的效力程度。此外，我们发现虽然 Glu 残基在保持手链环肽 cycloviolacin O2 的活性方面非常重要，但在 Möbius 环肽中则不那么重要。尽管环肽亚家族之间存在这些差异，但对环肽混合物的系统测试表明它们以相加的方式起作用。
