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Principal Investigator: ANEEL K. AGGARWAL
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2020
Award: $211,875
Funding agency: National Institute of Allergy and Infectious Diseases
The Flavivirus genus includes mosquito-borne human pathogens, such as dengue virus, yellow fever virus,
and the Zika virus (ZIKV), among others. ZIKV's recent spread in Americas and its link to microcephaly in
newborn infants and the Guillan-Barré syndrome in adults has invigorated efforts to develop a vaccine, as well
as measures to eradicate the Aedes mosquito vectors. In addition to these measures, it is equally important 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. As a step towards this goal, we have determined several high-resolution crystal
structures of the ZIKV NS5-MTase. Together, these structures (all determined to better than 1.5 Å in
resolution) provide a powerful new framework for the design and synthesis of small molecules that selectively
target MTase from ZIKV and other pathogenic flaviviruses. In aim 1, we will a) use the structural information to
design S-adenosylmethionine (SAM) based analogs with the capacity to interact with unique amino acids in
ZIKV MTase, and which extend deeper into the RNA binding tunnel to block RNA binding. We will also design
analogs with substituents on both the adenine base and the methionine portion of SAM to provide additional
selectivity against the human RNA 5'-cap MTases. We will b) chemically synthesize the analogs and produce
them to a purity of 95% for in vitro and cell-based assays, as well as for cocrystallization with the ZIKV NS5-
MTase. 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). Together, the proposed studies will help to identify new small molecules that can be
potentially developed into inhibitors of ZIKV NS5-MTase.
Terms: <0-4 weeks old><1H-Purin-6-amine><21+ years old><5' Capped RNA><5' mRNA Cap Structure><Address><Ademetionine><Adenine><AdoMet><Adult><Adult Human><Aedes><Americas><Amino Acids><Antibody-Dependent Enhancement><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Attenuated><Binding><Binding Sites><Bioassay><Biologic Assays><Biological Assay><Biophysics><Breakbone Fever Virus><Cell Body><Cell Components><Cell Structure><Cells><Cellular Structures><Chemicals><Cocrystallization><Cocrystallography><Combining Site><Crystallization><Defect><Dengue Virus><Dengue fever virus><Development><Disease Outbreaks><Drug Design><EC 2.1.1><Event><Flavivirus><Genetic Alteration><Genetic Change><Genetic defect><Geographic Area><Geographic Locations><Geographic Region><Geographical Location><Goals><Group B Arbovirus><Guanosine 5'-Diphosphate><Guanosine Diphosphate><HCV><HCV/HIV><HIV and HCV><HIV and hepatitis C><HIV-HCV><HIV/HCV><HIV/Hepatitis C><Health><Hepatitis C virus><Human><In Vitro><Laboratories><Lead><Life Cycle><Life Cycle Stages><Link><Measures><Medicinal Chemistry><Methionine><Methylation><Methyltransferase><Microcephaly><Modern Man><Molecular Interaction><Mutation><Newborn Infant><Newborns><Non-structural Protein><Nonstructural Protein><Outbreaks><Pathogenicity><Pb element><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Process><Property><RNA Binding><RNA Caps><RNA bound><RNA methylation><Reactive Site><Research><Resolution><S-Adenosylmethionine><SAMe><Structure><Structure-Activity Relationship><Syndrome><Testing><Vaccination><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Replication><Vitamin B4><Yellow fever virus><ZIKA><ZIKV><Zika Virus><adulthood><aminoacid><analog><anti-viral agents><anti-viral drugs><anti-virals><base><biophysical foundation><biophysical principles><biophysical sciences><chemical structure function><chemical synthesis><design><designing><develop a vaccine><development of a vaccine><developmental><genome mutation><geographic site><guided discovery><guided inquiry><heavy metal Pb><heavy metal lead><human pathogen><inhibitor><inhibitor/antagonist><life course><methylase><micrencephaly><microencephaly><mosquito-borne><mosquitoborne><newborn child><newborn children><novel><public health emergency><s-adenosyl-l-methionine><scaffold><scaffolding><small molecule><structural biology><structure function relationship><transmethylase><vaccine development><vaccine formulation><vector mosquito><viral RNA><viral multiplication><viral replication><virology><virus RNA><virus multiplication><virus protein><zikav>