Conformational Design of Cyclic Peptides

本项目将开发和测试在构象水平上设计环肽的方法。环肽可以具有高的生物活性，这是由于它们的3D结构。然而，预测这种结构是困难的，由于环化所施加的构象约束，和许多自由度仍然可用的分子。该项目将通过计算和实验相结合的方案来解决这个问题。在第一种情况下，将解决具有较高（例如C3或C4）对称性的环肽。局部肽构象的信息将从天然蛋白质结构中收集，并用于生成模型，这将支持化学合成和结构分析的目标识别。溶液中的构象将通过NMR实验和其他生物物理方法（包括圆二色谱法）进行鉴定。实验信息将被反馈以改进模型构建协议。这种工作流程将产生新的方法，将允许在构象水平上设计环肽。这些方法将应用于超分子化学的挑战，例如在新的高度特异性的客体结合大环化合物的设计，以及在化学生物学中，例如在能够干扰蛋白质-蛋白质相互作用的环肽的设计。这里的核心工作将与EPSRC的几个关键学科领域保持一致，最值得注意的是化学生物学主题。

This project will develop and test methods for designing cyclic peptides at the conformational level. Cyclic peptides can have high biological activity, which is due to their 3D structure. However, predicting this structure is difficult due to the conformational constraints imposed by cyclisation, and the many degrees of freedom still available to the molecule. This project will address this through a combined computational and experimental programme. In the first instance, cyclic peptides with higher (e.g. C3 or C4) symmetry will be addressed. Information on local peptide conformation will be gleaned from natural protein structures and used to generate models, which will support the identification of targets for chemical synthesis and structural analysis. Conformations in solution will be identified via NMR experiments and other biophysical methods, including circular dichroism spectroscopy. Experimental information will be fed back to improve the model-building protocols. This workflow will give rise to new methods that will allow the design of cyclic peptides at the conformational level. These methods will be applied to challenges in supramolecular chemistry, for example in the design of new highly-specific guest-binding macrocycles, and in chemical biology, for example in the design of cyclic peptides that are capable of interfering with protein-protein interactions. The core work here will be in keeping with several key EPSRC subject areas, most notably the Chemical Biology theme.