Use of Human Lung Tissue Models for Screening of Drugs against SARS-CoV-2 Infection

Abstract

The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given circa 7817 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies than in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both SARS-CoV-2 Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus, has virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.

Gravity-perfused airway-on-a-chip optimized for quantitative BSL-3 studies of SARS-CoV-2 infection: barrier permeability, cytokine production, immunohistochemistry, and viral load assays

“…Having succeeded in validating our novel airway chip, we were ready to test its reliability for modeling infectious disease by infecting it with SARS-CoV-2 in an actual BSL-3 space with live virus. While some groups have conducted studies using pseudoviruses or BSL-2-appropriate coronaviruses, 42–44 these options obviously come with limitations with regard to providing direct information on SARS-CoV-2 itself. By utilizing the Italian strain of SARS-CoV-2 and demonstrating the ability to transfer the chips into a BSL-3 space, we were able to establish both infection of the airway epithelium and a transfer of infection to the airway endothelium, resulting in a marked increase in proinflammatory cytokines from both spaces within the airway chip and thus recapitulating key features of COVID-19 in a human cell-based airway chip.…”

Use of Stem Cell-Derived Cardiomyocyte and Nasal Epithelium Models to Establish a Multi-Tissue Model Platform to Validate Repurposed Drugs Against SARS-CoV-2 Infection

“…Virus stocks used in our previous study, [13], were used again for this work. In brief, Delta (B.1.617.…”

“…Prospective drugs were down-selected from the Compounds Australia Open Drug collection using a set of filters described previously [12]. Based on the results of our previous study using a human airway tissue model, fluvoxamine, everolimus, pyrimethamine, aprepitant, and sirolimus were tested alongside the control drugs remdesivir, molnupiravir, and nirmatrelvir (PF-07321332; the active ingredient in Paxlovid) [13]. All of the drugs were obtained from Selleck Chemicals (Houston, TX, USA) or Sigma Aldrich (St Louis, MO, USA).…”

“…We have recently employed an in silico approach to down-select nine approved drugs (plus three anti-SARS-CoV-2 control drugs) for assessment using a commercially-sourced ALI model of the human airway epithelium [11][12][13]. Five drugs that showed promise were further evaluated against both Delta and Omicron variants of concern (VOC), with fluvoxamine exhibiting anti-SARS-CoV-2 activity, albeit at concentrations higher than can be achieved in patients [13].…”

Molecular Docking and Dynamics Identifies Potential Repurposed Drug Candidates for COVID-19 Studies

“…However, a major challenge is that there are 7,817 candidates in Compounds Australia open drug collection, so we recently developed a database to down-select the top candidates in a systematic manner [17,18]. To validate our approach experimentally, 12 of the top 214 drugs, along with the current standards of care (remdesivir, molnupiravir and nirmatrelvir/ritonavir), were recently subjected to in vitro evaluation of anti-viral efficacy against SARS-CoV-2 Delta and Omicron variants of concern [19]. To decide which additional candidates from the list of 214 drugs should be evaluated next, this paper reports an in silico approach consisting of molecular docking studies followed by molecular dynamic studies.…”