2 However, the current mode of treatment is not equally effective for all HCV genotypes and significant Palbociclib molecular weight side effects are still observed. Efforts are currently being made to develop a combination of new direct-acting antivirals (DAAs) not leading to the emergence of escape

mutations and, if possible, free of IFN. First proofs of concept recently emerged from clinical trials demonstrating that combinations of DAAs can result in the cure of chronic HCV infection.3, 4 However, combinations of drugs targeting different steps of the viral life cycle, including virus entry, will likely improve viral response rates and therapeutic success. HCV is a small enveloped virus with a positive stranded RNA genome belonging to the Hepacivirus genus in the Flaviviridae family.5 Its genome encodes two envelope glycoproteins (E1 and E2), which play a key role in virus entry into the hepatocyte. However, as a result of its association with low- or very-low-density lipoproteins,6 the lipoprotein moiety can also play a role in the entry process of HCV particle. HCV entry is currently viewed as a complex multistep process, because a series of specific cellular entry factors have been shown to be essential in the early steps of the HCV life cycle.7 These molecules include the CT99021 scavenger receptor class B type 1 (SRB1), the tetraspanin CD81,

tight-junction proteins claudin 1 (CLDN1) and occludin (OCLN), and receptor tyrosine kinase-like epidermal growth factor receptor. After its interaction with entry factors at the cell surface, HCV particle is internalized by clathrin-mediated endocytosis.8 Importantly, as for several other viruses, HCV can also spread Ribonucleotide reductase by direct cell-to-cell transfer.9, 10 3D, three-dimensional; Ab, antibody; BVDV, bovine viral diarrhea virus; CC50, 50% cytotoxic concentration; CI, combination index; CLD, chronic liver disease; CLDN1, claudin 1; CMFDA, 5-chloromethylfluorescein diacetate; CQ, chloroquine; DAAs, direct-acting antivirals; DMEM,

Dulbecco’s modified Eagle’s medium; DMSO, dimethyl sulfoxide; FCS, fetal calf serum; ffu, focus forming unit; FQ, ferroquine; gRNA, genomic RNA; HCV, hepatitis C virus; HCVcc, hepatitis C virus produced in cell culture; HCVpp, hepatitis C virus pseudoparticle; IC50, half-maximal inhibitory concentration; IC90, 90% inhibitory concentration; IF, immunofluorescence; IFN, interferon; JFH-1, Japanese fulminant hepatitis type 1; LT, liver transplantation; mAb, monoclonal Ab; OCLN, occludin; PE, phycoerythrin; Peg-IFN-α, pegylated interferon alpha; qRT-PCR, quantitative reverse-transcription polymerase chain reaction; RBV, ribavirin; SRB1, scavenger receptor class B type 1; YFV, yellow fever virus. Ferroquine (FQ; SSR97193) is a ferrocenic analog of chloroquine (CQ) that has been developed as a new antimalarial drug (Fig. 1A).