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Principal Investigator: ANEEL K. AGGARWAL
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2023
Award: $253,500
Funding agency: National Institute of Allergy and Infectious Diseases
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)
Terms: <0-4 weeks old><1H-Purin-6-amine><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><5' Capped RNA><5' mRNA Cap Structure><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adenine><Adult><Adult Human><Affinity><Americas><Amino Acids><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Attenuated><Binding><Binding Sites><Bioassay><Biologic Assays><Biological Assay><Biophysics><Breakbone Fever Virus><COVID-19 virus><COVID19 virus><Cell Body><Cells><Chemistry><CoV-2><CoV2><Combining Site><Crystallization><DENV><Defect><Dengue Virus><Dengue fever virus><Development><EC 2.1.1><Egypt 101 virus><Flavivirus><Genetic Alteration><Genetic Change><Genetic defect><Goals><Group B Arbovirus><HCV infection><HIV><Health><Hepatitis C><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Human><Human Immunodeficiency Viruses><In Vitro><LAV-HTLV-III><Lead><Life Cycle><Life Cycle Stages><Link><Lymphadenopathy-Associated Virus><Measures><Medicinal Chemistry><Methylation><Methyltransferase><Microcephaly><Modern Man><Molecular Interaction><Mutation><Newborn Infant><Newborns><Non-Polyadenylated RNA><Non-structural Protein><Nonstructural Protein><Pathogenicity><Pathology><Patients><Pb element><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Process><RNA><RNA Caps><RNA Gene Products><RNA methylation><Reactive Site><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Structure><Structure-Activity Relationship><Syndrome><Testing><Uganda><Vaccines><Vero Cells><Viral><Virus><Virus Replication><Virus-HIV><Vitamin B4><WNV><West Nile virus><Wuhan coronavirus><ZIKA><ZIKV><ZIKV infected><ZIKV infection><ZIKV positive><Zika Virus><Zika virus infection><adulthood><aminoacid><analog><anti-viral agents><anti-viral compound><anti-viral development><anti-viral drug development><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-viral therapeutic development><anti-viral therapy development><anti-virals><antiviral compound><antiviral development><antiviral drug development><antiviral medication><antiviral therapeutic><antiviral therapeutic development><antiviral therapy development><arthropod transmission><arthropod transmitted><arthropod-borne><arthropodborne><attenuate><attenuates><base><bases><biophysical foundation><biophysical principles><biophysical sciences><chemical structure function><chemical synthesis><cofactor><coronavirus disease 2019 virus><coronavirus disease-19 virus><design><designing><determine efficacy><develop a vaccine><develop vaccines><developing anti-viral agent><developing anti-viral drug><developing anti-viral therapeutic><developing anti-viral therapy><developing antiviral agent><developing antiviral drug><developing antiviral therapeutic><developing antiviral therapy><development of a vaccine><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><future outbreak><genome mutation><hCoV19><heavy metal Pb><heavy metal lead><hep C><hepatitis non A non B><human pathogen><infected with ZIKV><infected with zika><infection by hepatitis c virus><inhibitor><life course><member><methylase><micrencephaly><microencephaly><nCoV2><newborn child><newborn children><next outbreak><non A, non B hepatitis><non-A, non-B hepatitis><novel><pathogen><scaffold><scaffolding><structural biology><structure function relationship><transmethylase><vaccine development><viral RNA><viral multiplication><viral replication><virology><virus RNA><virus multiplication><zika infected><zika infection><zika viral infection><zikav>