Development of MS2045 for inhibition of Zika methyltransferase

开发用于抑制寨卡病毒甲基转移酶的 MS2045

• 批准号: 10645958
• 负责人: ANEEL K. AGGARWAL
• 金额: $ 25.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-02 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10645958
• 关键词: 2019-nCoV; Adenine; Adult; Affinity; Americas; Amino Acids; Antiviral Agents; Attenuated; Binding; Binding Sites; Biological Assay; Biophysics; Cells; Chemistry; Crystallization; Defect; Dengue Virus; Development; Flavivirus; Goals; HIV; Health; Hepatitis C; Human; In Vitro; Lead; Life Cycle Stages; Link; Measures; Methylation; Methyltransferase; Microcephaly; Mutation; Newborn Infant; Nonstructural Protein; Pathogenicity; Pathology; Patients; Pharmaceutical Chemistry; Process; RNA; RNA Caps; RNA methylation; Structure; Structure-Activity Relationship; Syndrome; Testing; Uganda; Vaccines; Vero Cells; Viral; Virus; Virus Replication; West Nile virus; ZIKA; ZIKV infection; Zika Virus; analog; antiviral drug development; arthropod-borne; base; chemical synthesis; cofactor; design; efficacy evaluation; future outbreak; human pathogen; inhibitor; member; novel; pathogen; scaffold; structural biology; vaccine development; viral RNA; virology

Project Summary The Zika virus (ZIKV) is a member of the Flavivirus genus that includes other arthropod-borne human pathogens such as dengue virus and West Nile virus, among others. ZIKV’s link to microcephaly in newborn infants and the Guillan-Barré syndrome in adults has invigorated measures to develop a vaccine, as well as efforts to develop antivirals based on targeting enzymatic activities central to the life cycle and survival of ZIKV. One such enzymatic activity is encoded by the methyltransferase (MTase) domain, located at the N-terminus of the nonstructural protein NS5. Taking a structure informed approach, we have succeeded in identifying a novel “lead-like” compound (MS2045) for the inhibition of ZIKV’s NS5 MTase activity and for blocking its replication. MS2045 provides a basis for further chemistry and the development of even more potent inhibitors. In aim 1, we will a) design MS2045 analogs with the capacity to establish specific interactions with unique amino acids of ZIKV MTase as a means to provide additional selectivity against the human RNA 5’-cap MTases; b) chemically synthesize these analogs and produce them to a purity of 95% for in vitro and cell-based assays, and for structural studies. In aim 2, we will a) perform biophysical assays to assess the ability of these analogs to selectively bind the ZIKV NS5-MTase as compared to the human RNA 5’-cap MTases and test their ability to inhibit RNA methylation; b) test these analogs in viral cell-based assays to assess their efficacy in blocking viral replication; c) determine structures ZIKV NS5-Mtase with select analogs for additional, iterative rounds of structure activity relationships (SARs). Collectively, these studies will help to identify analogs of MS2045 that can be potentially developed into potent and selective inhibitors of NS5-MTase from ZIKV (and other pathogenic flaviviruses)

项目概要 寨卡病毒 (ZIKV) 是黄病毒属的一员，该属还包括其他节肢动物传播的人类病原体 例如登革热病毒和西尼罗河病毒等。 ZIKV 与新生儿小头畸形的联系以及 成人吉兰-巴利综合征激发了开发疫苗的措施以及开发疫苗的努力 基于针对 ZIKV 生命周期和生存至关重要的酶活性的抗病毒药物。这样的一位 酶活性由位于 N 端的甲基转移酶 (MTase) 结构域编码。 非结构蛋白 NS5。采用结构知情的方法，我们成功地确定了一种新颖的 “类先导”化合物 (MS2045)，用于抑制 ZIKV 的 NS5 MTase 活性并阻止其复制。 MS2045 为进一步化学和开发更有效的抑制剂奠定了基础。在目标 1 中， 我们将 a) 设计 MS2045 类似物，使其能够与独特的氨基酸建立特定的相互作用 ZIKV MTase 作为一种针对人类 RNA 5'-cap MTase 提供额外选择性的方法； b) 化学方法 合成这些类似物并生产出纯度为 95% 的产品，用于体外和基于细胞的测定，以及 结构研究。在目标 2 中，我们将 a) 进行生物物理测定，以评估这些类似物的能力 与人类 RNA 5'-cap MTase 相比，选择性结合 ZIKV NS5-MTase 并测试它们的能力 抑制RNA甲基化； b) 在基于病毒细胞的测定中测试这些类似物，以评估它们阻断病毒的功效 复制； c) 确定 ZIKV NS5-Mtase 的结构以及选择的类似物，以进行额外的迭代 结构活动关系（SAR）。总的来说，这些研究将有助于识别 MS2045 的类似物 可以开发成 ZIKV（和其他致病性病毒）NS5-MTase 的有效和选择性抑制剂 黄病毒）