How drug repurposing helped in fighting Covid-19

Recently a team of researchers from the Perelman School of Medicine at the University of Pennsylvania found nine new potential Covid-19 treatments after conducting ‘drug repurposing’ screens. Among the nine, three already had approval from the Food and Drug Administration to treat other diseases. These are cyclosporine, a drug used to prevent organ rejection in those who have undergone a liver, kidney or heart transplant; dacomitinib, a cancer drug; and salinomycin, an antibiotic.

Drug repurposing (also called drug repositioning, reprofiling or re-tasking) is a strategy to identify new therapeutic uses for old or already available drugs. Some well-known examples of repurposed drugs are hydroxychloroquine (HCQ), remdesivir and avifavir/favipiravir.

Drug repurposing has been one of the most active areas of pharmacology in the last decade. Compared to traditional drug development methods, repurposing allows substantially cheap methods in discovering new treatments. Artificial intelligence and machine learning play a crucial role in accelerating drug repurposing for Covid-19.

The Perelman team, whose findings were published in Cell Reports, screened thousands of existing drugs and drug-like molecules for their ability to stop the replication of the coronavirus. The team tested the drug molecules for anti-coronaviral activity in a variety of cell types, including human airway-lining cells.

As part of the screening project, the team assembled a library of 3,059 compounds. This includes about 1,000 FDA-approved drugs and more than 2,000 drug-like molecules. The initial round of antiviral screening was performed on African Green Monkey kidney cells and a cell line derived from human liver cells.

The team identified that several compounds worked in the monkey kidney cells, and 23, including HCQ, worked in the human liver cells. Since Covid-19 mainly affects the respiratory system, and the virus is thought to initiate its attack via airway-lining cells, the researchers wanted to do the next round of experiments on a respiratory cell type. They eventually identified Calu-3, derived from human airway-lining cells, as a suitable cell line for the test. The antiviral compounds identified through the human liver cell screen were then tested on Calu-3. The team found that only nine drugs had activity in these cells. The nine did not include HCQ.

The study revealed that SARS-CoV-2 uses a different mechanism to gain entry to respiratory cells when compared with kidney or liver cells. In kidney and liver cells, HCQ has the potential to act as an agent to disrupt viral activity. But in respiratory cells, the mechanism of the virus is different, which makes HCQ an unsuccessful candidate to stop the viral activity.

The Perelman team highlights cyclosporine as particularly promising against Covid-19— the drug was found to work against SARS-CoV-2 in both respiratory and non-respiratory cells. It employs two distinct mechanisms for this: by inhibiting cyclophilins, the cell
enzymes that are hijacked by the coronavirus for its benefit; and by suppressing the potentially lethal inflammation caused by a severe virus attack.