Document text
Principal Investigator: DONALD E INGBER
Organization: HARVARD UNIVERSITY
Fiscal Year: 2020
Award: $928,351
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
This COMPETITIVE REVISION application is being submitted to expand the scope of our ongoing NIH
grant UH3HL141797 in order to leverage our human organ-on-a-chip (Organ Chip) microfluidic culture devices
for the rapid development and assessment of potential therapeutic agents for COVID-19. Our ongoing UH3
grant supports the development of human Lung Chips as in vitro preclinical tools for rapid discovery of new
therapeutics for viral pandemics caused by influenza. In recent studies, we showed that highly differentiated
human cells in our Lung Chips, as well as human intestinal cells within Intestine Chips we developed, express
high levels of ACE2 and TMPRSS2 that mediate SARS-CoV-2 virus (CoV2) infection. We also were able to
infect these Organ Chips with CoV2 spike protein-expressing viral pseudoparticles (CoV2pp) that closely mimic
the effects of native CoV2 virus when tested against multiple FDA approved drugs in cell-based assays.
Human Lung Chips were also shown to be more stringent models for assessing potential COVID19 inhibitory
activity as only a subset of these drugs significantly inhibited entry of the CoV2pp when administered under
flow on-chip at their maximum concentration (Cmax) in human blood reported in clinical studies. Here, we
propose to use human Intestine and Lung Chips in combination with computational discovery and synthetic
chemistry approaches to develop broad-spectrum coronavirus therapeutics that would both help infected
COVID19 patients now, and allow us to be prepared to prevent infections by related pandemic viruses that
emerge in the future. In preliminary studies, multiple novel compounds designed with our computational tools
exhibited significant inhibitory activities when tested against both CoV2pp and native CoV2 virus in cell based
assays. Thus, our Specific Aims include: 1) to use computational and synthetic chemistry approaches to
create new compounds that are predicted to inhibit infection by CoV2 virus and related coronaviruses, 2) to
prioritize active molecules by analyzing their structure-activity relationships in cell-based assays infected with
native CoV2 and related coronaviruses, 3) to identify lead compounds and effective doses based on inhibition
of infection and host inflammatory responses in human Organ Chips using native coronaviruses, and 4) to
carry out pharmacokinetic studies in mice coupled with iterative chemical synthesis and testing in cell-based
assays to optimize the pharmaceutical properties and safety of the lead compounds, while retaining efficacy.
Through this effort, we will identify new compounds that demonstrate broad spectrum inhibiting activities
against CoV2 as well as related coronaviruses, and generate pharmacokinetic data necessary to move these
drugs into animal validation studies and, eventually, human clinical trials. This work will also further establish
the value of human Organ Chips as preclinical tools for accelerating drug development.
Terms: <2019 novel coronavirus><2019-nCoV><3-D><3-Dimensional><3D><Animals><Apical><Assay><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Reticuloendothelial System><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Line><Cell Lineage><CellLine><Cells><Clinical Research><Clinical Study><Clinical Trials><Coronaviridae><Coronavirus><Coupled><Data><Development><Devices><Disease model><Doctor of Philosophy><Dose><Drug Kinetics><Drug Therapy><Drugs><Epithelial><Epitheliasin Gene><Epithelium><Epithelium Part><Exhibits><FDA approved><Funding><Future><Grant><Grippe><Human><Immune><Immunes><In Vitro><Incidence><Infection><Infection prevention><Inflammation><Inflammatory Response><Influenza><Intestinal><Intestines><Investigators><Lead><Lung><Lung Respiratory System><Lung infections><Maryland><Mediating><Medication><Mice><Mice Mammals><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Microfluidics><Modeling><Modern Man><Molecular Dynamics Simulation><Mucous body substance><Mucus><Murine><Mus><NIH><National Institutes of Health><Organ><Organoids><PRSS10><Patients><Pb element><Ph.D.><PhD><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Pharmacotherapy><Prevent infection><Production><Property><Proteins><Public Health><Receptor Protein><Reporting><Research Personnel><Researchers><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Safety><Severe acute respiratory syndrome coronavirus 2><Strains Cell Lines><Structure><Structure-Activity Relationship><Surface><Synthesis Chemistry><Synthetic Chemistry><TMPRSS2><TMPRSS2 gene><Technology><Testing><Therapeutic><Therapeutic Agents><Tissue Arrays><Tissue Chip><Tissue Microarray><United States National Institutes of Health><Villus><Viral><Viral Diseases><Virulence><Virus><Virus Diseases><Work><Wuhan coronavirus><base><bowel><chemical informatics><chemical structure function><chemical synthesis><cheminformatics><computational chemistry><computational pipelines><computational tools><computerized tools><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><cultured cell line><cytokine><design><designing><developmental><disorder model><drug development><drug treatment><drug/agent><efficacy testing><flu infection><gastrointestinal symptom><heavy metal Pb><heavy metal lead><influenza infection><inhibitor><inhibitor/antagonist><intestinal epithelium><medical college><medical schools><microfluidic chip><molecular dynamics><molecular shape><mucous><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><organ on a chip><organ on chip><pandemic><pandemic disease><pre-clinical><preclinical><pulmonary><pulmonary infections><receptor><recruit><response><school of medicine><structure function relationship><three dimensional><tool><validation studies><viral infection><virus infection><virus-induced disease><µfluidic>