Fragment-based drug design and substrate envelope model of the Zika virus protease

基于片段的药物设计和寨卡病毒蛋白酶的底物包膜模型

• 批准号: 9976338
• 负责人: Jacqueto Zephyr
• 金额: $ 3.02万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-17 至 2022-02-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976338
• 关键词: Active Sites; Acute; Address; Adult; Affinity; Amino Acid Sequence; Antiviral Agents; Basic Amino Acids; Binding; Biological Assay; Cells; Chemicals; Cleaved cell; Clinical; Complex; Computational Biology; Conscience; Consensus; Crystallization; Crystallography; Drug Design; Drug resistance; Enzyme Inhibition; Enzymes; Flavivirus; Guillain-Barré Syndrome; HIV; Human; Knowledge; Lead; Mentors; Microcephaly; Modeling; Molecular; Mutate; Mutation; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Polyproteins; Populations at Risk; Protease Inhibitor; Proteins; RNA Viruses; Research; Resistance; Role; Shapes; Site; Structure; Testing; Therapeutic; Time; Vaccines; Variant; Viral; Virulent; Virus; ZIKA; ZIKV infection; Zika Virus; base; design; drug development; drug discovery; experience; human disease; in silico; infection risk; inhibitor/antagonist; mosquito-borne; neonate; nervous system disorder; novel; peptidomimetics; pre-clinical; pressure; programs; scaffold; screening; structural biology; therapeutic target; tool; transmission process

Project Summary Zika virus (ZIKV) is a mosquito-borne virus that causes severe neurological diseases such as microcephaly in neonates and Guillain-Barre syndrome in adults. ZIKV is also a global threat with a large at-risk population in the tropical and subtropical regions. Furthermore, non-vector borne transmission allows ZIKV to infect people worldwide. There are neither direct-acting antivirals nor vaccines available against Zika. The ZIKV NS2B-NS3 protease is an attractive therapeutic target because of its essential role in viral maturation. The current peptidomimetic inhibitors of the ZIKV protease suffer from poor cellular potency and nonselective inhibition of human proteases. The limitations of these peptidomimetic inhibitors are a result of their peptide scaffold and covalent warhead groups used to increase their potency. Hence, there is a need to discover clinically viable protease inhibitors (PIs) to generate lead compounds for further drug development. Fragment-based drug design (FBDD) is a promising approach for discovering novel scaffolds to overcome the limitations of peptidomimetics. This project aims to identify clinically viable ZIKV PIs using FBDD. I hypothesize that FBDD will result in potent and selective ZIKV PIs. Moreover, how the ZIKV protease recognizes diverse substrates remains unknown. Similar observations of diverse substrates recognition by other viral proteases led to the discovery of the substrate envelope (SE) model, which states that the conscience volume the diverse substrates occupy within the active site of a protease is the mode of recognition. I hypothesize that the SE model can explain diverse substrate recognition by the ZIKV protease. The SE model also explained the structural basis of drug resistance for those viral proteases. PIs that bind within the consensus volume of the substrates, i.e. the substrate envelope, are less susceptible to drug resistance. Drug resistance is the biggest problem facing direct-acting antivirals targeting viral proteases of other highly mutating viruses. Therefore, the problem of drug resistance must be addressed at the early stages of drug discovery. This proposal allows the unique opportunity to incorporate the ZIKV SE model into the FBDD approach to preemptively address the problem of drug resistance. Hence, the ZIKV SE can be a structural tool to guide inhibitor design. To investigate these hypotheses, I will leverage my expertise in medicinal chemistry and structural biology to rationally design, synthesize and evaluate the ZIKV PIs. I will rely on my experience in crystallography and computational biology to solve co-crystal structures of the ZIKV protease with inhibitors and substrates, respectively. From the protease-substrate complex structures, I will generate a ZIKV protease SE. The results from this project will provide an understanding of the structural basis of diverse substrate recognition by the ZIKV protease, and also generate clinically viable PIs for further drug development.

项目概要 寨卡病毒（ZIKV）是一种由蚊子传播的病毒，可导致严重的神经系统疾病，例如小头畸形 新生儿和成人格林巴利综合征。 ZIKV 也是一种全球性威胁，在该地区有大量高危人群 热带和亚热带地区。此外，非媒介传播使 ZIKV 能够感染人类 全世界。既没有直接作用的抗病毒药物，也没有针对寨卡病毒的疫苗。 ZIKV NS2B-NS3 蛋白酶是一个有吸引力的治疗靶点，因为它在病毒成熟中发挥着重要作用。目前的 ZIKV 蛋白酶的拟肽抑制剂的细胞效力较差且非选择性抑制 人类蛋白酶。这些拟肽抑制剂的局限性是由于它们的肽支架和 共价弹头基团用于增强其威力。因此，有必要发现临床上可行的 蛋白酶抑制剂 (PI) 生成先导化合物，用于进一步的药物开发。基于片段的药物 设计（FBDD）是一种有前途的方法，用于发现新颖的支架来克服现有技术的局限性 肽模拟物。该项目旨在使用 FBDD 识别临床上可行的 ZIKV PI。我假设 FBDD 将产生有效且选择性的 ZIKV PI。此外，ZIKV 蛋白酶如何识别不同的底物 仍然未知。对其他病毒蛋白酶识别不同底物的类似观察导致 发现基质包络（SE）模型，该模型指出良心体积不同 底物占据蛋白酶的活性位点是识别模式。我假设 SE 模型可以解释 ZIKV 蛋白酶对多种底物的识别。 SE 模型还解释了 这些病毒蛋白酶的耐药性的结构基础。在共识量内绑定的 PI 基质，即基质包膜，不易产生耐药性。耐药性是最大的 针对其他高度突变病毒的病毒蛋白酶的直接作用抗病毒药物面临的问题。因此， 耐药性问题必须在药物发现的早期阶段得到解决。该提案允许 将 ZIKV SE 模型纳入 FBDD 方法的独特机会，可以抢先解决 耐药性问题。因此，ZIKV SE 可以成为指导抑制剂设计的结构工具。到 研究这些假设，我将利用我在药物化学和结构生物学方面的专业知识 合理设计、综合和评估 ZIKV PI。我将依靠我在晶体学方面的经验 计算生物学解决 ZIKV 蛋白酶与抑制剂和底物的共晶结构， 分别。根据蛋白酶-底物复合物结构，我将生成 ZIKV 蛋白酶 SE。结果 该项目将提供对不同底物识别的结构基础的理解 ZIKV 蛋白酶，还可以生成临床上可行的 PI，用于进一步的药物开发。