Non-Nucleotide RNA-Dependent RNA Polymerase Inhibitor That Blocks SARS-CoV-2 Replication

Abstract

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.

Quercetin and luteolin are single-digit micromolar inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase

“…These compounds may serve as a starting point for the development of newer molecular entities with greater efficacy and affinity, and with fewer side effects 21 . Recently some examples of natural products with appreciable inhibition potency against SARS-CoV-2 RdRp include lycorine and corilagin 22 – 24 . Also, luteolin and quercetin, which are two ancestors of flavonoid compounds, are known for having a range of basal pharmacological activities that, in addition to their well-established anti-inflammatory properties, have demonstrated antiviral properties against picornavirus (RNA virus) and DNA viruses, such as hepatitis B virus, herpes simplex, and adenovirus 25 – 27 .…”

A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases

“…The SARS-CoV-2 RdRp is a heterotrimeric protein complex composed of nsp7, nsp8 and nsp12. We prepared this RdRp recombinantly, as reported before [ 21 ], and measured the inhibitory activity of PR673. Indeed, it targeted the SARS-CoV-2 RdRp: the synthesis of RNA was totally blocked at a PR673 concentration above 12.5 µM ( Figure 2 , SARS-CoV-2 panel).…”

“…NS5 proteins and SARS-CoV-2 nsp12, nsp8 and nsp7 were expressed with appropriate purification and folding tags, as detailed in Supplementary Table S1 and as described before [ 21 , 35 , 39 ]. Briefly, all of the proteins were expressed in bacterial cells, except for the full length nsp12 protein, which was expressed in insect cells.…”

“…Importantly, new SARS-CoV-2 variants, such as omicron, that partially escape vaccine-induced immunity are sensitive to these compounds [12]. In addition, other coronaviral enzymes, including exonuclease, endonuclease, helicase and methyltransferase, have recently been biochemically and structurally described [13][14][15][16][17], and their inhibitors have been reported [18][19][20][21]; however, none of these compounds have been developed enough to enter clinical trials. Furthermore, often, the simultaneous administration of several compounds is necessary to efficiently combat a virus and to prevent the development of escape mutants, as illustrated by the highly efficient highly active antiretroviral therapy (HAART) against the HIV virus [22].…”

Discovery of 2-Phenylquinolines with Broad-Spectrum Anti-coronavirus Activity

“…Recently, many quinoline and quinazoline derivatives have been tested in a cell-based SARS-CoV-2 RdRp reporter system, with a few quinolines being active. 29 This prompted us to investigate the most potent 2-PhQs (compounds 6f , g , 7k , and 9j ) as potential SARS-CoV-2 RdRp inhibitors via a fluorescent-based assay, including non-nucleotide inhibitor F243 30 as a positive control. All the tested compounds lacked activity against RdRp at the highest tested concentration of 30 μM ( Table 3 ).…”