Although effective vaccines against COVID-19 already exist, the lack of effective antiviral drugs that can prevent SARS-CoV-2 virus infection or stop the development of COVID-19 disease has prompted Calibr (California Institute for Biomedical Research) and Scripps Research to test more than 12,000 drugs in two different types of human cells infected with SARS-CoV-2. The drugs used in the study were taken from the ReFRAME library which is formulated by Calibr in 2018 with the support of the Bill & Melinda Gates Foundation, founded to address urgent medical problems. This collection contains drugs approved by the US Food and Drug Administration (FDA) as well as other experimental compounds that are in different phases of clinical trials. A screen of this library resulted in 90 existing approved drugs and/or drug candidates at different phases of clinical trials. Out of these 90, 13 molecules had the greatest repurposing potential to therapy for COVID-19. Four drugs approved by the US Food and Drug Administration have been identified – halofantrine, nelfinavir, simeprevir and manidipine, and the remaining nine are in different phases of clinical trials.

Some of the most effective antiviral strategies are ‘cocktails’ in which patients are given several different drugs to combat infection, such as those used to treat HIV infections. Therefore, in this study, the researchers re-examined the ReFRAME library of compounds in the presence of low concentrations (80 M) of remdesivir (Veklury®), an antiviral drug manufactured by the pharmaceutical company Gilead, and approved by the US Food and Drug Administration as a therapy for COVID-19. The results of this study resulted in 19 drugs with an additive effect when administered with remdesivir. The advantage of a therapeutic strategy that uses a combination of drugs is that taking a lower dose of any drug from the administered “cocktail” could reduce the risk of side effects of that drug. Combinations of drugs can also slow the development of drug resistance. Out of these 19 drugs, particularly noteworthy are the nucleoside analogue riboprin (previously formulated as a compound for the treatment of nausea and Surgical site infections) and the folate antagonist 10-deazaaminopterin (an antineoplastic compound currently in phase II of drug development). These two drugs could potentially be administered with remdesivir to increase the overall safety and efficacy of the treatment, to reduce side effects as well as to slow development of drug resistance.

The results of this study were published June 3 in the journal Nature Communications.

Assist. Prof. Aleksandra Maršavelski, PhD
Specialist in computational biochemistry
Faculty of Science
Zagreb, Croatia