Developing New Tools for the Chemical Diversification of Peptide Scaffolds

肽是开发针对多种疾病的新药的有用先导。它们占据了小分子和抗体之间的化学空间，因此它们可以选择性地抑制这些其他分子不能抑制的靶标。在肽领域内，开发肽支架的化学多样化的路线是相当感兴趣的，因为这允许克服体内稳定性等挑战。我们将开发新的合成化学，可用于化学多样化的肽支架。具体来说，我们将开发合成方法来化学修饰“天然”肽，目的是改善其生物和物理特性。然后，建立的化学将用于修改和增强先前由Kawamura教授（纽卡斯尔）确定的“前导肽”的特性。它也将被利用在新的配体的新出现的癌症靶点与教授华林（纽卡斯尔）的准备。 工作点1：全氟化氨基酸的制备：作为开发获得新型氨基酸的新方法的计划的一部分，我们最近开发了全氟杂芳族化合物，如五氟吡啶，以获得一系列新型氟化氨基酸[例如，https://www.cobbgroupdurham.com/ Org.Biomol. Chem 2019，Org. Biomol. Chem 2017]。我们将设计可用作19 F NMR探针的氟化氨基酸，作为肽的选择性化学修饰或获得新型环肽支架的反应手柄。 WP 2：电化学在肽科学中的应用：使用电化学有机合成技术来功能化氨基酸或大的复杂生物分子，如肽，还有待探索。我们将使用电化学来修饰和功能化单个氨基酸和完整的肽。 WP 3：评估新型氨基酸在生物学背景下的作用Kawamura小组已经确定了针对一系列生物医学重要蛋白质的活性肽（例如Nat. Comm，2017）。我们将新的氨基酸（WP 1，WP 2）纳入选定的命中肽序列，并评估对靶亲和力，细胞渗透性和生物活性的影响。此外，在纽卡斯尔癌症药物发现组中，已经鉴定了一系列迄今为止涉及蛋白质-蛋白质相互作用的难治性癌症靶点。作为相关MoSMed项目（Waring）的一部分，将鉴定新型命中肽，并将制备的一系列新型氨基酸纳入其中。

Peptides are useful leads for the development of new drugs against a wide range of diseases. They occupy the chemical space between small molecules and antibodies and as such they can selectively inhibit targets that these other molecules cannot. Within the peptide field developing routes for the chemical diversification of peptide scaffolds is of considerable interest as this allows challenges like in vivo stability to be overcome. We will develop new synthetic chemistry that can be used to chemically diversify peptide scaffolds. Specifically, we will develop synthetic approaches to chemically modify "natural" peptides with the aim of improving their biological and physical properties. The chemistry established will then be utilized to modify and enhance the properties of "lead peptides" previously identified by Prof Kawamura (Newcastle). It will also be exploited in the preparation of novel ligands for emerging cancer targets with Professor Waring (Newcastle). WP1: Preparation of Perfluorinated Amino Acids: As part of a program to develop new approaches to accessing novel amino acids we recently exploited perfluoroheteroaromatics, such as pentafluoropyridine, to access a range of novel fluorinated amino acids [e.g. https://www.cobbgroupdurham.com/ Org. Biomol. Chem 2019, Org. Biomol. Chem 2017]. We will design fluorinated amino acids that can be used as 19F NMR probes, as reactive handles for the selective chemical modification of peptides or to access novel cyclic peptide scaffolds. WP2: The Application of Electrochemistry in Peptide Science: The use of electrochemical organic synthetic techniques to functionalise amino acids or large complex bio-molecules such as peptides is yet to be explored. We will use electrochemistry to modify and functionalise both single amino acids and full peptides. WP3: Assessing the Effect of Novel Amino Acids in a Biological Context The Kawamura group has identified active peptides against a range of biomedically important proteins (e.g. Nat. Comm, 2017). We will incorporate novel amino acids (WP1, WP2) into selected hit peptide sequences and assess the effect on target affinity, cellular permeability and bioactivity. In addition within the Newcastle Cancer Drug Discovery Group a range of thus far intractable cancer targets involving protein-protein interactions have been identified. As part of a related MoSMed project (Waring), novel hit peptides will be identified and into these we will incorporate a range of the novel amino acids prepared.