Inhibitors Targeting Hepatitis C Virus (HCV) Entry

Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems, such as fibrosis, steatosis, and cirrhosis, in addition to progressing to hepatocellular carcinoma and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system’s activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC⁵⁰ and CC⁵⁰ values of 0.25 nM and >10 μM (SI: 10,000), respectively. This SRBI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC⁵⁰ and CC⁵⁰ values of 0.0331 and 25.1 μM, respectively), as well as in NPC1L1 (IC⁵⁰ and CC⁵⁰ values of 2.3 nM and > 15 μM, respectively). Thus, this review will discuss promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions, and advances in this field.