Development of new serine protease inhibitors by optimisation of rationally designed covalent S1 fragments

丝氨酸蛋白酶是一种在蛋白质中切割肽键的酶，其中丝氨酸在活性位点内充当亲核氨基酸。抑制丝氨酸蛋白酶的新型口服药物的发现已被证明在平衡碱性和高电离官能团的要求方面存在问题，这是生物活性与口服吸收所必需的（Drag na . rev . dd 2010）。在x射线结构工作的指导下，该项目将研究新型非碱性化合物的设计和有机合成，这些化合物与蛋白酶S1结合袋内的氨基酸相互作用，产生用于片段优化的高效配体分子（Ghosh 2015）。将选择官能团从碎片延伸到催化氧阴离子孔中，通过合成合理设计的化学弹头（Traube Eur），得到一系列慢速/共价抑制剂。江铃汽车2014)。在该项目的初始阶段，将合成血浆钾化管抑制剂，因为已经证明血浆钾化管系统的过度活性会导致遗传性血管性水肿，并且还与糖尿病黄斑水肿、脑出血和其他炎症性疾病密切相关（Teufel JMC 2018）。在该项目的第二阶段，发现的原理将应用于血栓、炎症、抗微生物和癌症领域的其他治疗重要和结构相关的胰蛋白酶样蛋白酶靶点。该多学科项目将以合成化学为重点，学生将获得现代合成有机/药物化学中使用的关键实验技术和设备的培训。成功完成多步骤合成策略的关键试剂开发，随后是产品分离/纯化和所有新产品的明确鉴定，将确保学生精通现代化学方法的运行和解释。计算化学将用于指导目标分子的设计，并预测结合到丝氨酸蛋白酶活性位点的配体的新相互作用位点。生成的化合物将需要完整的药理学表征（在KalVista进行实物表征），因此该项目的多学科性质将为学生提供药物化学的几个领域的洞察力，以及启动自己的学术或制药行业职业生涯所需的关键技能。

Serine proteases are enzymes that cleave peptide bonds in proteins, where the serine serves as the nucleophilic amino acid within the active site. The discovery of new oral drugs to inhibit serine proteases has proven problematic with the requirement to balance basic and highly ionised functional groups, required for biological activity with oral absorption (Drag Nat.Rev.DD 2010). Guided by X-Ray structural work, the project will investigate the design and organic synthesis of novel non-basic compounds that interact with amino acids within the protease S1 binding pocket to generate highly ligand-efficient molecules for fragment-based optimisation (Ghosh 2015). Functional groups will be chosen to extend from the fragments into the catalytic oxyanion hole to give series of slow off-rate/covalent inhibitors through the synthesis of rationally-designed chemical warheads (Traube Eur.JMC 2014). In the initial arm of the project, inhibitors of plasma kallikrein will be synthesised as it has been shown that excessive activity of the plasma kallikrein system contributes to hereditary angioedema and is also strongly implicated in diabetic macular edema, cerebral hemorrhage, and other inflammatory disorders (Teufel JMC 2018). In a second phase of the project, principles discovered will be applied to other therapeutically-important and structurally-related trypsin-like protease targets in the thrombosis, inflammation, anti-microbial and cancer areas. The multi-disciplinary project will have a strong synthetic chemistry focus, with the student gaining training on key experimental techniques and equipment employed in modern synthetic organic/medicinal chemistry. The critical exploitation of reagents for the successful completion of multi-step synthetic strategies followed by product isolation/purification and the unambiguous identification of all new products will ensure the student becomes proficient in the running and interpretation of modern chemistry methods. Computational chemistry will be used to guide the design of the target molecules and predict new interaction sites for ligands bound into the serine protease active site. The generated compounds will require full pharmacological characterization (performed in-kind at KalVista), therefore the multidisciplinary nature of this project will provide the student insight into several areas of medicinal chemistry, key skills required to launch their own academic or pharmaceutical industry career.