Repurposing FDA-Approved Drugs for Treatment of 2019-nCoV-induced Disease

Lead Research Organisation: Queen's University of Belfast

Abstract

SARS/CoV-2 was recently identified as the cause of the outbreak of pneumonia first detected in Wuhan, China in December 2019. Current efforts are focused on containment and separation of infected individuals, with no registered drugs for the treatment of COVID-19. Hence, drugs that have been registered for the treatment of other coronavirus conditions might be used (off-label) in an attempt to save the lives of COVID-19 patients. As development of vaccines and drugs for prevention and treatment of SARS-CoV-2 infection have been brought to priority status by WHO and governments, numerous drug studies are moving forward. Drug repurposing is defined as the application of known drugs to new indications. This approach is attractive, as repurposed drugs have already passed toxicity trials. Therefore, we aim to screen clinically approved drugs either as single or pair combinations for the therapeutic development of antiviral and anti-inflammatory agents to control and treat COVID-19 disease. We strongly anticipate the data generated will identify novel single or synergistic drug pairs, lead to detailed pre-clinical evaluation and provide the impetus for rapid progress to clinical trials or compassionate use in extreme cases.

Technical Summary

This COVID-19 Rapid Response award is jointly funded (50:50) between the Medical Research Council and the National Institute for Health Research. The figure displayed is the total award amount of the two funders combined, with each partner contributing equally towards the project.

A novel coronavirus (SARS-CoV-2) originating in Wuhan, China has reached pandemic status and causes a disease termed COVID-19. Therapeutics and vaccines are urgently needed. The normal pace of new drug development is incompatible with strategies to rapidly combat COVID-19. Drug combinations with antiviral and anti-inflammatory activity will likely be essential to treat infected patients, as acute respiratory virus-induced disease is commonly mediated by inflammatory responses to infection.
An alternative strategy to rapidly identify therapeutics to combat SARS-CoV-2 is drug repurposing. As the drugs are already FDA-approved, it is cost-effective and time-efficient. To this end, we will exploit MuSIC (multiplex screening of interacting compounds) screening of a unique library consisting of ~1,000 drugs to identify single and synergistic interacting compounds that have either SARS-CoV-2 antiviral activity or anti-inflammatory activities, with limited/no toxicities. This library includes FDA-approved compounds and antiviral drugs that showed activity against other cornoviruses (SARS-CoV & MERS-CoV) (1). Drug candidates will be validated using SARS-CoV-2-infection of well-differentiated primary human airway epithelial cell cultures (WD-PAECs), which are excellent surrogates of human airway epithelium. WD-PAECs represent the most relevant pre-clinical translational model for screening therapeutic drugs for COVID-19. SARS-CoV-2 uses that same receptor/entry factors as SARS-CoV (2), which infects WD-PAEC cultures. Our findings will identify candidate drugs for treating COVID-19 patients, which can quickly enter clinical trials or be employed for compassionate use, especially in the case of viral diseases lacking specific treatments.
(1): Mani et al. J Young Pharm, 2019; 11(2) : 117-121
(2): Hoffmann et al. bioRxiv https:

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