Broad-spectrum inhibition of coronavirus main and papain-like proteases by HCV drugs

Abstract

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has led to over 200,000 deaths thus far. We screened a library of approved antiviral drugs against the two SARS-CoV-2 proteases, 3C-like/main protease (3CLpro/Mpro) and papain-like protease (PLpro), which are essential for viral replication and attractive drug targets. Three HCV protease inhibitors were tested and found to inhibit 3CLpro and PLpro enzymes from Alpha-, Beta- and Gamma-coronaviruses. Anti-HIV drugs had no activity. Boceprevir and telaprevir inhibited 3CLpro, with boceprevir inhibiting eight of nine coronavirus 3CLpro enzymes tested including from SARS-CoV-2, MERS and SARS-CoV. Asunaprevir inhibited PLpro from SARS-CoV-2 and four other coronaviruses. The 1.4 Å X-ray structure of boceprevir bound to 3CLpro was determined to explain its broad-spectrum activity and guide structure-based design of inhibitors of multiple coronaviruses.Authors Brandon J. Anson, Mackenzie E. Chapman, and Emma K. Lendy contributed equally to this work.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

“…However, the addition of 1 to 100 µM famotidine to the reaction does not signi cantly reduce the amount of ISG15 cleaved during the assay ( Figure 1, lanes 4 to 6), thus suggesting that famotidine does not inhibit SARS-CoV-2 PLpro. A previous virtual screening report 26 suggested that famotidine might bind to the 3 chymotrypsinlike protease (3CLpro), more commonly referred to as the main protease (Mpro), however this mechanism was recently discounted 27 .…”

“…proteases (PLpro or Mpro) 27 . Vero E6-based cell assays also indicate that famotidine has no direct antiviral activity in this cell line, although antiviral activity in cells that express H 2 has not been tested.…”

Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases

“…In the course of our study, three other groups reported that boceprevir can inhibit SARSCoV2 M pro at low micromolar concentrations in vitro (48)(49)(50). Two of these studies included crystal structures of SARSCoV2 M pro complexed with boceprevir (PDB 6WNP and 7C6S) that validate our manually docked model (49,50).…”

“…In the course of our study, three other groups reported that boceprevir can inhibit SARSCoV2 M pro at low micromolar concentrations in vitro (48)(49)(50). Two of these studies included crystal structures of SARSCoV2 M pro complexed with boceprevir (PDB 6WNP and 7C6S) that validate our manually docked model (49,50). Alignment of these structures to that of 13b complexed with SARSCoV2 M pro indicates that the proline ring of boceprevir can indeed mimic a turn taken by the backbone of linear protease inhibitors at the P2 position ( Supporting Fig 4), confirming our original hypothesis (Fig.…”

“…1). Two of the studies also demonstrated that boceprevir suppresses SARSCoV2 viral replication in monkey cells with EC50 values between 2 and 16 µM (48,50).…”