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Principal Investigator: Lijun Rong
Organization: CHICAGO BIOSOLUTIONS, INC.
Fiscal Year: 2019
Award: $972,475
Funding agency: National Institute of Allergy and Infectious Diseases
Ebola (EBOV) and Marburg (MARV) viruses belong to the Filoviridae family and can cause fatal
hemorrhagic fevers characterized by widespread tissue destruction after an incubation period of
4-14 days. Due to safety concerns, these viruses are designated as biosafety level 4 agents.
Currently, there is no effective vaccine or therapeutic treatment for filoviral infections in humans.
Africa has recently (2014-2016) suffered a lethal EBOV epidemic with 27,000 people infected
and more than11,000 deaths, underscoring the urgency of antiviral drug discovery and
development. This Phase II application proposes to develop potent, small molecule inhibitors,
which block entry of EBOV. We have identified compounds that inhibit entry of infectious
EBOV/MARV with IC50 values in the nanomolar range. In Phase I, we synthesized structurally
diverse analogs of the anti-Ebola CBS1118 hit series based on structure-activity relationships
(SARs), to improve potency and selectivity. Prioritized inhibitors were validated in the infectious
assay. We investigated the mechanism of action (MOA) of selected candidates, and identified
druglike EBOV inhibitors with good in vitro ADME properties. In addition, these inhibitors display
excellent pharmacokinetic parameters in mouse studies, following oral administration. In this
application, we propose to accomplish the following three specific aims: (1) optimize the lead
scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of
the advanced lead compounds with EBOV glycoproteins; and (3) evaluate the in vivo efficacy
and pharmacokinetics/toxicokinetics of the advanced lead compounds.
Terms: <Address><Africa><African><Animal Model><Animal Models and Related Studies><Animals><Antidotes><Antiviral Agents><Antiviral Drugs><Antiviral Therapy><Antivirals><Assay><Back><Benzamides><Binding><Bioassay><Biochemical><Biologic Assays><Biological><Biological Assay><Biological Terrorism><Bioterrorism><Bleeding><Body Tissues><CDC><Categories><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Cessation of life><Characteristics><Clinic><Common Rat Strains><Cryo-electron Microscopy><Cryoelectron Microscopy><Crystallization><Death><Development><Disease><Disease Outbreaks><Disorder><Dorsum><Dose><Drug Design><Drug Kinetics><Drugs><EBOV><EBOV GP><Ebola><Ebola virus><Ebola virus GP gene product><Ebola virus envelope glycoprotein><Electron Cryomicroscopy><Epidemic><Escape Mutant><Evaluation><Exhibits><Exposure to><Family><Family member><Fever><Filoviridae><Filovirus><Frankfurt-Marburg Syndrome Virus><GP Ebola virus><General Viruses><Glycoproteins><Goals><Hemorrhage><Human><In Vitro><Infection><Lead><Life><Location><Marburg><Marburg virus><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medical><Medication><Medicinal Chemistry><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Oral Administration><Oral Drug Administration><Outbreaks><Pb element><Pharmaceutic Chemistry><Pharmaceutic Preparations><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Pharmacology><Phase><Prevalence><Property><Pyrexia><Rat><Rats Mammals><Rattus><Research><Route><Safety><Series><Single Crystal Diffraction><Structure><Structure-Activity Relationship><Symptoms><Therapeutic><Theriacs><Time><Tissues><Toxicokinetics><Treatment Efficacy><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><United States National Institutes of Health><VAC-TX><Vaccine Therapy><Vaccines><Viral Diseases><Viral Hemorrhagic Fevers><Virus><Virus Diseases><Virus Inhibitors><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><acute toxicity><analog><anti-viral agents><anti-viral drugs><anti-viral therapy><anti-virals><base><biodefense><blood loss><chemical structure function><cost effective><cryo-EM><cryoEM><design><designing><developmental><drug development><drug discovery><drug/agent><ebolavirus><efficacy evaluation><febrile><febris><genotoxicity><heavy metal Pb><heavy metal lead><hemorrhagic fever><improved><in vivo><in vivo evaluation><in vivo testing><inhibitor><inhibitor/antagonist><insight><intervention efficacy><intraoral drug delivery><lead optimization><model of animal><model organism><mortality><mouse model><murine model><mutant><nano-molar><nanomolar><non-human primate><nonhuman primate><novel><pathogen><pre-clinical><preclinical><prophylactic><safety study><safety testing><scaffold><scaffolding><scale up><small molecule><small molecule inhibitor><structure function relationship><therapeutic efficacy><therapeutic vaccination><therapeutically effective><therapy efficacy><viral infection><viral infectious disease treatment><viral inhibitor><virus infection><virus-induced disease>