Discovery of clinically approved drugs capable of inhibiting SARS-CoV-2 in vitro infection using a phenotypic screening strategy and network-analysis to predict their potential to treat covid-19

Abstract

<jats:p>The disease caused by SARS-CoV2, covid-19, rapidly spreads worldwide, causing the greatest threat to global public health in the last 100 years. This scenario has become catastrophic as there are no approved vaccines to prevent the disease, and the main measures to contain the virus transmission are confinement and social distancing. One priority strategy is based on drug repurposing by pursuing antiviral chemotherapy that can control transmission and prevent complications associated with covid-19. With this aim, we performed a high content screening assay for the discovery of anti-SARS-CoV-2 compounds. From the 65 screened compounds, we have found four drugs capable to selectively inhibit SARS-CoV-2 in vitro infection: brequinar, abiraterone acetate, neomycin, and the extract of Hedera helix. Brequinar and abiraterone acetate had higher inhibition potency against SARS-CoV-2 than neomycin and Hedera helix extract, respectively. Drugs with reported antiviral activity and in clinical trials for covid-19, chloroquine, ivermectin, and nitazoxanide, were also included in the screening, and the last two were found to be non-selective. We used a data mining approach to build drug- host molecules-biological function-disease networks to show in a holistic way how each compound is interconnected with host node molecules and virus infection, replication, inflammatory response, and cell apoptosis. In summary, the present manuscript identified four drugs with active inhibition effect on SARS-CoV-2 in vitro infection, and by network analysis, we provided new insights and starting points for the clinical evaluation and repurposing process to treat SARS-CoV-2 infection.</jats:p>

Drug Design and Repurposing with DockThor-VS Web Server: Virtual Screening focusing on SARS-CoV-2 Therapeutic Targets and their Non-Synonym Variants

“…Considering all targets and all drugs evaluated, we found that the majority of the predicted binding a nities are in the range of high to low micromolar a nity units (scores higher than -6.8 kcal/mol correspond to binding a nity values higher than ~ 10 µM, whereas scores lower than -8.2 kcal/mol corresponds to submicromolar a nities). This result is expected since many drugs under clinical trials exhibited no activity or only modest inhibitory effects in some experimental studies reported in the literature [69][70][71] . However, we found some interesting results that deserve to be highlighted.…”

Drug design and repurposing with DockThor-VS web server focusing on SARS-CoV-2 therapeutic targets and their non-synonym variants

“…1 www.nature.com/scientificreports/ submicromolar affinities). This result is expected since many drugs under clinical trials exhibited no activity or only modest inhibitory effects against SARS-CoV-2 in some experimental studies reported in the literature [79][80][81] . However, we found some interesting results that deserve to be highlighted.…”

Progress and pitfalls of a year of drug repurposing screens against COVID-19

“…Similar antiviral effects of ivermectin have been previously reported for a range of other viruses [ 61 ]. However, two basic parameters of antiviral drug development are overlooked in these studies: i) the allegedly “active” antiviral concentration of ivermectin is roughly equivalent to the known cytotoxic concentration in many cell lines, including Vero cells [ 61 , 62 • ], which confounds interpretation of a specific antiviral effect; and ii) human pharmacokinetic data for ivermectin reveal that this antiviral (and thus, cytotoxic) concentration is not reached in human plasma, which also explains the excellent safety profile of the drug when used as approved [ 59 •• , 63 , 64 ].…”