Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

Abstract

COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, therapeutics that can help manage the disease are still required until immunity has been achieved globally. The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in-line with reported proteinuria and liver damage in patients with COVID-19. Using the nano-luciferase as a measure of virus replication we identified 35 drugs that reduced replication in Vero cells and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.

Atovaquone and Berberine Chloride Reduce SARS-CoV-2 Replication In Vitro

“…Finally, we found that atovaquone is able to reduce the replication of SARS-CoV-2 in human lung cells and is able to slow infectious virus production in human airway epithelium cultures, yet had no impact in intestinal organoids. These results confirm the anti-SARS-CoV-2 activity of atovaquone as found in several previous studies [47,48]. However, interestingly, in contrast to the study by Carter-Timofte et al, who find a striking reduction in SARS-CoV-2 infection (approximately 6 logs in Vero cells and 4 logs in Calu3 cells), we observed roughly a 2-log decrease in Vero E6 and Calu3 cells.…”

“…Of the compounds tested, we found that both atovaquone and brequinar were able to reduce SARS-CoV-2 replication in Vero E6 cells. Both of these molecules are pyrimidine biosynthesis inhibitors and have been shown to inhibit the replication of SARS-CoV-2 and other viruses [13,16,17,[47][48][49][50][51]. These results suggest that pyrimidine biosynthesis is specifically important for SARS-CoV-2 biology since ribavirin, a purine biosynthesis inhibitor, had no impact on SARS-CoV-2 replication.…”

Preclinical Evaluation of Chicken Egg Yolk Antibody (IgY) Anti-RBD Spike SARS-CoV-2—A Candidate for Passive Immunization against COVID-19

“…The ongoing coronavirus disease 2019 (COVID- 19) is an extremely contagious and infectious viral illness induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The first cases of COVID-19 were announced on 31 December 2019 in Wuhan, China.…”

“…According to the official data released by the World Health Organization (WHO), the global crude mortality rate is approximately 3.9% [17]. To date, numerous COVID-19 vaccines (e.g., Moderna, Johnson & Johnson/Janssen, Sinovac, Pfizer-BioNTech, and AstraZeneca) are available in many countries, and these can significantly reduce the incidence and/or severity of symptoms and the mortality rate; however, there are still concerns regarding possible reduced vaccine efficacy, especially in the context of rapid virus mutation [18,19]. In addition, the lack of potent non-vaccine treatment underlines concerns about possible future outbreaks of emerging virus-related ailments.…”

Ongoing Use of SSRIs Does Not Alter Outcome in Hospitalized COVID-19 Patients: A Retrospective Analysis

“…The low cost and widespread availability of some drugs already on the market has made them attractive from a social and medical perspective. A number of anti-viral agents are under investigation, but are still pending formal approval in the United States [ 4 , 5 ]. Unfortunately, the true efficacy of some of these compounds has not been supported by more rigorous clinical trials [ 6 ].…”