Ferroquine for COVID-19

AbstractThe ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

The current pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) demands rapid identification of new antiviral molecules from the existing drugs. Drug repurposing is a significant alternative for pandemics and emerging diseases because of the availability of preclinical data, documented safety in clinic and possibility of immediate production and scalable capacity and supply. Several drugs such as ivermectin and hydroxy chloroquine have been repurposed as anti-SARS-CoV-2 agents, but the effect of these compounds in treating the COVID-19 patients remains sub-optimal. In the present study repurposed drug libraries consisting of 560 compounds from two different sources have been screened against SARS-CoV-2 isolate USA-WA1/2020 in Vero-E6 cell line and 24 compounds were found active. The SARS-CoV-2 virus propagated in Vero E6 cell line and used in screening the drug libraries was sequenced by Next Generation Sequencing to identify any mutations that may have accumulated in the virus genome. The whole genome sequencing data of SARS-CoV-2 showed 9 and 6 single nucleotide polymorphisms in spike protein with reference to Wuhan-Hu-1(NC045512.2) and USA/WA-CDC-WA1/2020 (MN985325.1) isolates respectively. The present study identified 24 compounds active against SARS-CoV-2 isolate USA-WA1/2020 out of 560 repurposed drugs from two libraries. The IC-50 values of the identified hits range from 0.4 µM to 16 µM. Further studies on the repurposed drugs identified in the present screen may be helpful in the rapid development of antiviral drugs against SARS-CoV-2.