Document text
Principal Investigator: HONGMIN LI
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2024
Award: $767,382
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract:
Flaviviruses are primarily insect-borne, associated with global morbidity and mortality, and found on every
inhabited continent. Unfortunately, current therapeutic options for treating diseases associated with these viruses
are limited. All flaviviruses encode methyltransferases (MTases)—flaviviral NS5 for both N-7 and 2'-O
methylations of viral genomic RNA. The N-7 MTase function is essential for replication of the viral RNA genome,
whereas 2'-O MTase function is required for the virus to evade the host innate immune response. These activities
are conserved among the flaviviruses. For this project, our collaborative team will optimize the current lead
compounds, perform high throughput screening (HTS) to identify additional lead candidates, chemically optimize
the lead candidates, and define structure activity relationships. Optimizing current lead compounds using cutting-
edge medicinal chemistry, the team will perform a large scale HTS campaign using innovative fluorescence
chemical probes to identify additional small molecule inhibitors of flavivirus RNA capping MTases. We will
perform an in-depth investigation of the model of action and antiviral efficacy using in vitro biochemistry, structural
biology, virology, in vivo pharmacokinetics, and in vivo animal models, which will allow the development of novel,
effective, broad-spectrum, and druglike therapeutic agents against both flaviviruses. Preliminary progress has
been made in the identification of initial lead inhibitors of these MTases, demonstrating low nanomolar antiviral
activity. We will advance these compounds to further develop potent antiviral compounds while conducting large-
scale screening in parallel for additional structural scaffold discoveries. Complementary expertise among our
investigators will synergize and expedite the progress of this research. Our collaborative objective is to provide
first-in-class drug candidates for the treatment or prevention of these viral infections.
Terms: <0-11 years old><0-4 weeks old><3-D><3-Dimensional><3D><5' Capped RNA><5' mRNA Cap Structure><Adverse effects><Animal Model><Animal Models and Related Studies><Annual Reports><Anti-viral Agents><Anti-viral Therapy><Arbovirus Encephalitis><Arthropod-Borne Encephalitis><Arthropod-Borne Viral Encephalitis><Assay><Binding><Bioassay><Biochemical><Biochemistry><Biological Assay><Biological Chemistry><Breakbone Fever Virus><Cell Body><Cells><Cellular Assay><Cessation of life><Chemicals><Child><Child Youth><Children (0-21)><Country><Crystallographies><Crystallography><DENV><DENV infection><DENV vaccine><Death><Dengue Infection><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus infection><Dengue virus vaccine><Development><Disease><Disease Outbreaks><Disorder><Drug Kinetics><Drugs><EC 2.1.1><Effectiveness><Egypt 101 virus><Enzyme Gene><Enzymes><Epidemic><Epidemic Encephalitis><FRET><Flavivirus><Flavivirus Infections><Fluorescence><Fluorescence Resonance Energy Transfer><Förster Resonance Energy Transfer><Genome><Group B Arbovirus><Groups at risk><High Throughput Assay><Human><Human Cell Line><In Vitro><Innate Immune Response><Insecta><Insects><Insects Invertebrates><Investigation><Investigators><Japanese B Encephalitis Virus><Japanese encephalitis virus><Label><Lead><Lytotoxicity><Medication><Medicinal Chemistry><Methods><Methylation><Methyltransferase><Microcephaly><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Newborn Infant><Newborns><Non-Polyadenylated RNA><Organoids><Orthoflavivirus><Outbreaks><Patients><Pb element><People at risk><Persons><Persons at risk><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacokinetics><Poison><Populations at Risk><Position><Positioning Attribute><Prevention><Public Health><RNA><RNA Caps><RNA Gene Products><RNA replication><Research><Research Personnel><Research Resources><Researchers><Resources><Ribonucleic Acid><Risk><Serotyping><Structure><Structure-Activity Relationship><Testing><Therapeutic><Therapeutic Agents><Toxic Chemical><Toxic Substance><Vaccination><Vaccines><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virus><Virus Diseases><Virus Replication><WNV><West Nile virus><Work><Yellow Fever Vaccine><Yellow Fever Virus Infection><Yellow fever virus><ZIKV><ZIKV infected><ZIKV infection><ZIKV positive><Zika Virus><Zika virus infection><analog><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral therapeutic><anti-virals><arboviral encephalitis><candidate validation><cell assay><chemical structure function><combat><cytotoxicity><dengue viral infection><design><designing><developmental><drug candidate><drug detection><drug testing><drug/agent><genomic RNA><heavy metal Pb><heavy metal lead><hesitant to vaccination><high throughput screening><human pathogen><in vivo><infected with ZIKV><infected with zika><inhibitor><innovate><innovation><innovative><insight><kids><lead candidate><lead optimization><methylase><micrencephaly><microencephaly><model of animal><mortality><mouse model><murine model><nano-molar><nanomolar><newborn child><newborn children><novel><scaffold><scaffolding><screening><screenings><small molecular inhibitor><small molecule inhibitor><structural biology><structure function relationship><synergism><three dimensional><tool><toxic compound><transmethylase><vaccination hesitancy><vaccine against DENV><vaccine against dengue><vaccine against yellow fever><vaccine candidate against dengue><vaccine hesitancy><vaccine hesitant><viral genomics><viral infection><viral infectious disease treatment><viral multiplication><viral replication><virology><virus genomics><virus infection><virus multiplication><virus-induced disease><yellow fever virus vaccine><youngster><zika infected><zika infection><zika viral infection><zikav>