# Lung-on-a-Chip Disease Models for Efficacy Testing (COVID-19 Competitive Revision)

> **NIH NIH UH3** · HARVARD UNIVERSITY · 2020 · $928,351

## Abstract

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.

## Key facts

- **NIH application ID:** 10167350
- **Project number:** 3UH3HL141797-04S1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** DONALD E INGBER
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $928,351
- **Award type:** 3
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167350

## Citation

> US National Institutes of Health, RePORTER application 10167350, Lung-on-a-Chip Disease Models for Efficacy Testing (COVID-19 Competitive Revision) (3UH3HL141797-04S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10167350. Licensed CC0.

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