Bivalent degraders of HCV NS3/4A protease complex for HCV infection

INDICATION: Hepatitis C virus (HCV)

Bivalent small molecules targeting the HCV NS3/4A protease complex and CRBN, which recruits E3 ubiquitin ligase and induces proteasomal degradation, could treat HCV. The molecules were generated by conjugating HCV drug Telavic telaprevir at its pyrazine ring to one of three CRBN-binding moieties, two of which are derivatives of cancer drugs Revlimid lenalidomide and Pomalyst pomalidomide. The three compounds inhibited the HCV NS3/4A protease complex in vitro with IC₅₀ values of 385, 296 and 247 nM and bound CRBN with EC₅₀ values of 576, 641 and 703 nM. In HCV-infected human cells, the compounds reduced viral replication with IC₅₀ values of 3.07 μM, 2.92 μM and 748 nM. Notably, one of the bivalent degraders inhibited viral replication in cells infected with two Telavic-resistant HCV strains...