By using computational analyses, scientists at the University of Cambridge have identified 200 approved drugs as possible candidates for repurposing against COVID-19 and validated two of them in early tests.
The two drugs, antimalarial therapy proguanil and rheumatoid arthritis medication sulfasalazine, showed they could safety inhibit the replication of the SARS-CoV-2 coronavirus behind COVID-19 in both monkey and human cell lines, according to a new study published in Science Advances.
Given both drugs are well established and well tolerated for other human diseases, they should be rapidly advanced into clinical trials to test whether they can prevent or treat COVID-19, the researchers proposed.
The Cambridge team started its research by mapping a network of human proteins that are induced by SARS-CoV-2 infection. The network included over 15,000 host proteins and represented nearly 583,000 interactions.
The researchers zeroed in on 476 key proteins most relevant in viral replication. Using computer simulations, they screened 1,917 approved drugs against the proteins, looking for candidates that could have stronger effects in blocking virus-induced changes.
The virtual screen returned 200 drugs that were predicted to target the key proteins. Among them, 40 are already in COVID-19 clinical trials and another 30 have previously been proposed as potential candidates against the disease, which the researchers said supported the strength of their approach.
Of the many proteins the 200 drugs bind to, the researchers noticed 30 proteins that are targeted by eight or more drugs. They found that all these proteins are related to the production of nitric oxide (NO)—which is known as an important element for viral synthesis—as well as a molecule called NADP, which also affects NO. This finding suggests that NO might be the mechanism by which these drugs work against viral infection, the researchers figured.
The team picked five drugs that operate within the NO pathway for further testing because of their good safety profiles.
In both monkey cell and human respiratory cell cultures, proguanil and sulfasalazine showed significant antiviral effects against SARS-CoV-2 without appearing to damage the cells at their indicated doses, the team reported.
Further analysis showed that both drugs affected an important component of the MAPK signaling pathway, which has been shown to be activated during SARS-CoV-2 infection and involved in inflammatory responses that pose a danger to patients. In lab experiments, the drugs significantly dialed down the cells’ expression of key cytokines involved in COVID-19, the team found.
Many drug development efforts around COVID have focused on repurposing existing medicines. Some of the promising candidates that scientists have recently proposed include low-cost leprosy drug clofazimine and Swiss biotech Polyphor’s investigational cancer drug balixafortide.
A research team at the University of Pennsylvania recently found that Pfizer’s lung cancer drug Vizimpro, the antibiotic salinomycin and anti-rejection therapy cyclosporine were effective against the coronavirus in human cell cultures.
The Cambridge team believes their data-driven approach offers a new resource for screening and repurposing drugs against COVID-19. Because COVID patients may have a broad range of underlying medical conditions, safety is an important consideration. There, both sulfasalazine and proguanil have the potential to be used to either prevent or treat the disease, the researchers said.
Because sulfasalazine is already being used for autoimmune disorders, the current study raises the possibility that it may have both antiviral and anti-inflammatory power against COVID, the researchers noted in the study. In the U.S., proguanil is combined with atovaquone and has an excellent safety profile when used as a prophylactic and in treatment of malaria, they said.