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

丝氨酸蛋白酶是切割蛋白质中的肽键的酶，其中丝氨酸充当活性位点内的亲核氨基酸。抑制丝氨酸蛋白酶的新型口服药物的发现已证明存在平衡碱性和高度电离官能团的要求的问题，这是口服吸收的生物活性所需的（Drag Nat.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结合口袋内的氨基酸相互作用，以产生高度配体效率的分子，用于基于片段的优化（Ghosh 2015）。将选择官能团从碎片延伸到催化含氧阴离子空穴，通过合成合理设计的化学弹头，产生一系列缓慢解离速率/共价抑制剂（Traube Eur.JMC 2014）。在该项目的初始阶段，将合成血浆激肽释放酶抑制剂，因为已证明血浆激肽释放酶系统的过度活性有助于遗传性血管性水肿，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形成，炎症，抗微生物和癌症领域的其他治疗重要性和结构相关的胰蛋白酶样蛋白酶靶标。该多学科项目将有一个强大的合成化学重点，与学生获得在现代合成有机/药物化学中使用的关键实验技术和设备的培训。成功完成多步合成策略的试剂的关键开发，然后是产品分离/纯化和所有新产品的明确识别，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靶分子的设计，并预测结合到丝氨酸蛋白酶活性位点的配体的新的相互作用位点。生成的化合物将需要完整的药理学表征（在KalVista进行实物），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见解，以及开展自己的学术或制药行业职业所需的关键技能。

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.