Quercetin and Luteolin Are Single-digit Micromolar Inhibitors of the SARS-CoV-2 RNA-dependent RNA Polymerase

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. Among the viral proteins, RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as one of the most promising targets for pharmacological intervention against SARS-CoV-2. To this end, we experimentally tested luteolin and quercetin for their ability to inhibit the RdRp enzyme. These two compounds are ancestors of flavonoid natural compounds known for a variety of basal pharmacological activities. Luteolin and quercetin returned a single-digit IC50 of 4.6 µM and 6.9 µM, respectively. Then, through dynamic docking simulations, we identified possible binding modes of these compounds to a recently published cryo-EM structure of RdRp. Collectively, these data indicate that these two compounds are a valid starting point for further optimization and development of a new class of RdRp inhibitors to treat SARS-CoV-2 and potentially other viral infections.

First study on in vitro antiviral and virucidal effects of flavonoids against feline infectious peritonitis virus at the early stage of infection

“…Similar results have been shown for influenza A virus [26], respiratory syncytial virus [27], and FMDV [35]. Luteolin had an inhibitory activity against SARS-CoV-2 RdRp with an IC 50 value of 4.6 µM [28]. In addition, a luteolin derivative, 7-methylluteolin, was found to be effective against FIPV 3CL pro with an IC 50 value of 28.5 ± 4.2 µM [17].…”

Singular Interface Dynamics of the SARS-CoV-2 Delta Variant Explained with Contact Perturbation Analysis

“…In the fight against the Covid-19 pandemic, molecular dynamics (MD) simulations were particularly successful at guiding vaccine development, , designing RNA polymerase inhibitors, investigating the binding of small molecules of the RBD, designing main protease inhibitors, and elucidating the role of glycans in SARS-CoV-2 viral entry . Notably, previous studies on the increased infectivity of variants investigated the role of mutations on antibody binding and uncovered an allosteric signaling between mutations in the Beta variant .…”