Proposed mechanism of synergy between HCV drugs and remdesivir
Proposed mechanism of synergy between HCV drugs, that inhibit SARS-CoV2 proteases, and the antiviral drug remdesivir, which inhibits the function of the SARS-CoV2 replicase

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.

Image of interdomain dynamis
The complex formed between MLV integrase and the chromosomal protein BRD3 creates an interdomain linker, which has restricted conformational flexiblity

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.