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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)

项目总结