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

基本信息

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
项目类别：
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

项目摘要

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)

项目摘要 Zika病毒（ZIKV）是包括其他节肢动物 - 传播人类病原体的黄病毒属的成员例如登革热病毒和西尼罗河病毒等。 ZIKV与新生婴儿的小头畸形的联系成年人的Guillan-Barré综合征已为开发疫苗的措施，并努力开发基于靶向酶促活性的抗病毒药物，是ZIKV生命周期和存活的中心。一个这样的酶活性由位于位于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部小说 “铅状”化合物（MS2045），用于抑制ZIKV的NS5 MTase活性并阻止其复制。 MS2045为进一步的化学和更多潜在抑制剂的发展提供了基础。在AIM 1中，我们将a）设计具有与独特的氨基酸建立特定相互作用的MS2045类似物 ZIKV MTase作为对人RNA 5'-CAP MTase提供额外选择性的手段； B）化学合成这些类似物，并将其产生为95％的纯度，用于基于细胞和细胞的测定结构研究。在AIM 2中，我们将a）进行生物物理评估，以评估这些类似物的能力与人RNA 5'-CAP MTase相比，有选择地结合ZIKV NS5-MTase，并测试其能力抑制RNA甲基化； b）在基于病毒细胞的测定中测试这些类似物，以评估其阻断病毒的效率复制； c）用选择的类似物来确定结构ZIKV NS5-mTase，以进行其他迭代回合结构活动关系（SARS）。总的来说，这些研究将有助于确定MS2045的类似物可以潜在地发展为ZIKV的NS5-mTase的潜在和选择性抑制剂（以及其他致病性黄病毒）