Developing New Tools for the Chemical Diversification of Peptide Scaffolds

开发肽支架化学多样化的新工具

• 批准号: 2448904
• 金额: --
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2448904
• 关键词: Developing; New; Tools; Chemical; Diversification

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.

多肽是开发治疗多种疾病的新药的有用线索。它们占据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无法抑制的靶点。在多肽领域中，开发多肽支架的化学多样化的路线是相当有兴趣的，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，可用于化学多样化的多肽支架。具体地说，我们将开发合成方法来对“天然”多肽进行化学修饰，目的是改善它们的生物学和物理性质。然后，所建立的化学将被用来修饰和增强先前由Kawamura教授(纽卡斯尔)确定的“铅多肽”的性质。它还将被用于与韦林教授(纽卡斯尔)一起为新出现的癌症靶点准备新的配体。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，我们最近利用全氟杂芳烃，如五氟吡啶，来获得一系列新型的氟化氨基酸[例如，https://www.cobbgroupdurham.com/组织。生物醇。化学2019，组织生物醇。Chem 2017]。我们将设计可用作19F核磁共振探针的氟化氨基酸，用作多肽选择性化学修饰的反应手柄，或用于获得新型环肽支架。WP2：电化学在多肽科学中的应用：使用电化学有机合成技术使氨基酸或大型复杂生物分子(如多肽)功能化仍有待探索。我们将使用电化学对单一氨基酸和全肽进行修饰和功能化。WP3：评估新氨基酸在生物学背景下的效果川村小组已经确定了针对一系列生物医学重要蛋白质(例如NAT)的活性多肽。通讯，2017)。我们将把新的氨基酸(WP1，WP2)整合到选定的HIT多肽序列中，并评估其对靶向亲和力、细胞通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-蛋白质相互作用的难治癌症靶点。作为一个相关的MoSMed项目(WARING)的一部分，将识别新的热门多肽，我们将在这些多肽中加入一系列制备的新氨基酸。