Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Abstract

Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.

Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2

“…3), including drugs that have been found in multiple SARS-CoV-2 repurposing studies, we investigated the prevalence of phospholipidosis-inducing CADs among 1,974 repurposing hits identified in the literature. We focused on 12 studies, including two screens of the ReFRAME library (24,25), screens of the NCATS "approved drug" and "bioactive" libraries (15), among others (3,14,16,22,(26)(27)(28)(29)(30).…”

“…CADs have in vitro activity against multiple viruses including Severe Acute Respiratory Syndrome, Middle East Respiratory Syndrome, Ebola, Zika, Dengue, and filoviruses (9), though CAD-induction of phospholipidosis has only been proposed as an antiviral mechanism for Marburg virus (10). Finally, among the most potent known phospholipidosis inducers are amiodarone (11) and chloroquine (12, 13), which are also potent inhibitors of SARS-CoV-2 replication in vitro (14)(15)(16), while drugs from SARS-CoV-2 phenotypic screens, such as chlorpromazine (17) and tamoxifen (16), are also known to induce phospholipidosis (18). As an effect that rarely occurs at concentrations lower than 100 nM, that does not appear to translate from in vitro to in vivo antiviral activity, and that can result in dose-limiting toxicity (19), phospholipidosis may be a confound to true antiviral drug discovery.…”

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

“…Among the 231 articles (PubMed and Google Scholar), 91 were retained [ 3 , 12 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ,…”

Hybrid In Silico Approach Reveals Novel Inhibitors of Multiple SARS-CoV-2 Variants

“…The cytopathic effect (CPE) of SARS-CoV-2 was measured in Vero-E6 cells in a BSL-3 facility as described previously. 10 Cells were harvested, resuspended at 160 000 cells/mL in assay media (minimal essential medium, MEM, 2% (v/v) heat inactivated fetal bovine serum, FBS, 1% 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, HEPES, 1% Pen/Strep/GlutaMax), and inoculated with SARS-CoV-2 (USA_WA1/2020) at a multiplicity of infection (MOI) of 0.002. Twenty-five microliters of the cell–virus mixture was dispensed per well of an assay-ready 384-well plate (Greiner, #781091).…”