Developing New Tools for the Chemical Diversification of Peptide Scaffolds

多肽是开发针对多种疾病的新药的有用线索。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其他分子无法抑制的目标。在多肽领域，开发多肽支架化学多样化的途径是相当有趣的，因为这可以克服体内稳定性等挑战。我们将开发新的合成化学，可用于化学多样化肽支架。具体来说，我们将开发合成方法来化学修饰“天然”肽，以改善其生物和物理特性。建立的化学物质将被用来修饰和增强川村教授（纽卡斯尔）先前确定的“导联肽”的性质。与沃林教授（纽卡斯尔）合作，还将开发用于新出现的癌症靶点的新型配体的制备。WP1：全氟化氨基酸的制备：作为开发获取新型氨基酸新方法方案的一部分，我们最近利用全氟杂芳烃，如五氟吡啶，来获取一系列新型氟化氨基酸[例如https://www.cobbgroupdurham.com/ Org]。Biomol。化学2019，Org。Biomol。化学2017]。我们将设计可以用作19F核磁共振探针的氟化氨基酸，作为选择性化学修饰肽的反应手柄或获得新的环状肽支架。WP2：电化学在多肽科学中的应用：电化学有机合成技术在氨基酸或大型复杂生物分子（如肽）功能化方面的应用尚待探索。我们将使用电化学来修饰和功能化单氨基酸和全肽。Kawamura小组已经确定了针对一系列生物医学上重要蛋白质的活性肽（例如Nat. Comm, 2017）。我们将把新的氨基酸（WP1, WP2）加入到选定的命中肽序列中，并评估其对靶标亲和力、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小组内，已经确定了一系列迄今为止涉及蛋白质-蛋白质相互作用的棘手癌症靶点。作为相关MoSMed项目（Waring）的一部分，将鉴定新的击中肽，并将其纳入一系列制备的新氨基酸。

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.