Hepatitis C virus drugs synergize with remdesivir to suppress SARS-CoV-2 replication
Effective control of COVID-19 requires antivirals directed against SARS-CoV-2 virus. We assessed ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS- CoV-2 Mpro and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the Mpro binding cleft. Seven of these HCV drugs also inhibit SARS-CoV-2 Mpro protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in cell culture, Some of these drugs also synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold. Careful examination of these data suggests that these HCV drugs also function through a second target. Surprisingly, some of these HCV drugs were found to also bind to and inhibit the SARS-CoV-2 PLpro protease. The synergistic activity of HCV drugs with remdesivir correlates with their ability to inhibit PLpro, indicating this function is the primary basis for their synergy with remdesivir.
A common binding motif in the ET domain of BRD3 forms polymorphic structural interfaces with host and viral proteins
The extra-terminal (ET) domain of BRD3 is conserved among BET proteins (BRD2, BRD3, BRD4), interacting with multiple host and viral protein-protein networks. Solution NMR studies of complexes formed between BRD3-ET domain with either the 79-residue murine leukemia virus integrase (IN) C-terminal domain (IN329-408), or its 22-residue IN tail peptide (TP) (IN386-407) alone, reveal reveal a 10-residue linker region (IN379-388) tethering the SH3 domain (IN329-378) to the ET-binding motif (IN389-405)-ET complex. This linker has restricted flexibility, impacting the potential range of interdomain orientations in the IN – nucleosome complex.