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Principal Investigator: Jun Wang
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2024
Award: $755,280
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Non-polio enteroviruses (NPEVs) are etiological agents for several human diseases including respiratory
infections, hand-foot-and-mouth disease (HFMD), aseptic meningitis, encephalitis, neonatal sepsis,
myocarditis, conjunctivitis, and acute flaccid paralysis. Among the more than 100 serotypes of NPEVs, some of
the most significant pathogens are enterovirus D68 (EV-D68), enterovirus A71 (EV-A71) and coxsackievirus B3
(CV-B3). According to CDC, these NPEVs combined have caused 10 to 15 million infections and tens of
thousands of hospitalizations in the U.S. Clearly, NPEVs are a public concern for both U.S. and the world.
No vaccines are available in the U.S. for the NPEVs such as EV-D68, EV-A71, and CV-B3. Three
inactivated EV-A71 vaccines are available in China. However, there are not broadly protective, and the efficacy
is limited to certain strains. There is no FDA-approved antiviral for any of these NPEVs. Thus, there is a
pressing need to develop orally bioavailable pan-enterovirus antivirals.
This proposal focuses on targeting the enterovirus nonstructural 2C protein for the development of orally
bioavailable broad-spectrum NPEV antivirals. Specifically, in Aim 1, we will optimize the antiviral activity and
pharmacokinetic properties of three series of 2C inhibitors. In Aim 2, we will determine the high-resolution X-
ray crystal structures of EV-A71, EV-D68, and CV-B3 2C proteins with structurally disparate 2C inhibitors. In
Aim 3, we will evaluate the in vivo antiviral efficacy of 2C inhibitors in EV-D68 and EV-A71 infection mouse
models. Successful implementation of this proposal will provide orally bioavailable broad-spectrum NPEV drug
candidates for further development.
Terms: <0-11 years old><Acute><Airway infections><Anti-viral Agents><Antiproteases><Aseptic Meningitis><Asia><Assay><Binding><Bioassay><Bioavailability><Biological Assay><Biological Availability><Brain Inflammation><Capsid><Causality><Cell Culture Techniques><Child><Child Youth><Children (0-21)><China><Clinical><Combined Modality Therapy><Complex><Conjunctivitis><Coxsackie Viruses><Coxsackievirus><Data><Development><Disease><Disease Outbreaks><Disorder><Disparate><Drug Design><Drug Kinetics><Drug Targeting><Drug resistance><Drugs><EV-68><EV-71><EV-A71><EV-D68><Echo Viruses><Echovirus><Encephalitis><Endopeptidase Inhibitors><Ensure><Enterovirus><Enterovirus 68><Enterovirus 71><Enterovirus A71><Enterovirus D68><Enterovirus Infections><Etiology><FDA approved><Fluoxetin><Fluoxetine><Foot Diseases><Goals><Grant><Hand's disease><Hand, Foot and Mouth Disease><Hospital Admission><Hospitalization><In Vitro><In vivo analysis><Infant><Infection><Knowledge><Lead><Mainland China><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medication><Meningitis><Mice><Mice Mammals><Molecular Interaction><Morbidity><Morbidity - disease rate><Mouth Diseases><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myocarditis><NIAID><National Institute of Allergy and Infectious Disease><Neonatal><Neurologic><Neurological><Oral><Oral Cavity Disease><Oral Cavity Disorder><Oral Disease><Oral Disorder><Organelles><Outbreaks><Palsy><Paralysed><Pb element><Peptidase Inhibitors><Peptide Hydrolase Inhibitors><Peptide Peptidohydrolase Inhibitors><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Physiologic Availability><Plegia><Polymerase><Prevention><Property><Protease Antagonists><Protease Inhibitor><Proteinase Inhibitors><Proteins><Prozac><Publications><RNA chemical synthesis><RNA synthesis><Resistance><Resolution><Respiratory Infections><Respiratory Tract Infections><Rhinovirus><Roentgen Rays><Role><Safety><Scientific Publication><Series><Serotyping><Structure><Supportive Therapy><Supportive care><Testing><United States><Vaccines><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virus Diseases><X-Radiation><X-Ray Radiation><X-ray><Xray><access to vaccination><access to vaccines><acute flaccid myelitis><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral therapeutic><anti-virals><cardiac inflammation><causation><cell culture><cell cultures><clinical significance><clinically significant><combination therapy><combined modality treatment><combined treatment><developmental><disease causation><drug candidate><drug discovery><drug resistant><drug/agent><efficacy study><heavy metal Pb><heavy metal lead><human disease><human pathogen><improved><in vivo><in vivo evaluation><in vivo testing><indexing><inhibitor><kids><lead candidate><lead optimization><mortality><mouse model><mouth disorder><multi-modal therapy><multi-modal treatment><murine model><mutant><nano-molar><nanomolar><neonatal sepsis><pan-enterovirus><paralysis><paralytic><pathogen><priority pathogen><recombinant virus><resistance to Drug><resistant><resistant to Drug><resolutions><respiratory><reverse genetics><small molecule><social role><vaccination access><vaccination availability><vaccine access><vaccine availability><viral RNA><viral infection><virology><virus RNA><virus infection><virus-induced disease><youngster>