Key result
RNase A inhibitors reduce SARS-CoV infectivity up to ~26-fold by inhibiting Nsp15 endoribonuclease activity.
Why the study?
The SARS-CoV Nsp15 endoribonuclease is an unusual RNA processing enzyme with a structurally similar active site to RNase A, suggesting RNase A inhibitors may inhibit Nsp15 activity.
Effect estimate: IC50 0.2 µM to 40 µM; infectivity reduced 8- to 26-fold
Small molecule RNase A inhibitors, including Benzopurpurin B and congo red, effectively inhibit SARS-CoV Nsp15 endoribonuclease activity and reduce viral infectivity in vitro.
Does not support clinical use; leaves open Nsp15 as a target for future coronavirus antivirals.
The severe acute respiratory syndrome (SARS) virus encodes several unusual RNA processing enzymes, including Nsp15, an endoribonuclease that preferentially cleaves 3’ of uridylates through a ribonuclease A (RNase A)-like mechanism. Crystal structures of Nsp15 confirmed that the Nsp15 active site is structurally similar to that of RNase A. These similarities and our molecular docking analysis lead us to hypothesize that previously characterized RNase A inhibitors will also inhibit the SARS-CoV Nsp15. Benzopurpurin B, C-467929, C-473872, N-306711, N-65828, N-103019 and congo red were tested for effects on Nsp15 endoribonuclease activity. A fluorescence assay revealed that the IC 50 values for inhibiting endoribonuclease activity were between 0.2 µM and 40 µM. These compounds were demonstrated to bind SARS-CoV Nsp15 by a differential scanning fluorimetry assay. Benzopurpurin B also inhibited the endoribonuclease activities of the Nsp15 orthologs from two other coronaviruses: mouse hepatitis virus (MHV) and infectious bronchitis virus (IBV). Benzopurpurin B, C-473872, and congo red reduced infectivity of MHV in L2 cells by 8- to 26- fold. The more effective drugs caused a decrease in MHV RNA accumulation. All three compounds reduced the infectivity of the SARS-CoV in Vero cells.
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A 2010 study studied SARS-CoV infection. RNase A inhibitors (Benzopurpurin B, C-467929, C-473872, N-306711, N-65828, N-103019, congo red) was evaluated on Nsp15 endoribonuclease activity inhibition and viral infectivity (IC50 0.2 µM to 40 µM; infectivity reduced 8- to 26-fold). Small molecule RNase A inhibitors, including Benzopurpurin B and congo red, inhibited SARS-CoV Nsp15 endoribonuclease activity (IC50 0.2-40 µM) and reduced viral infectivity by 8- to 26-fold.
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