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Updated: Jul 24, 2025
Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds
Published on: October 29, 2015
Inhibitors Targeting Hepatitis C Virus (HCV) Entry
Paulo Fernando da Silva Santos-Júnior1, João Xavier de Araújo-Júnior1,2, Edeildo Ferreira da Silva-Júnior1
1Institute of Chemistry and Biotechnology, Federal University of Alagoas, Campus A.C. Simões, LourivalMeloMota Avenue, Maceió, 57072-970, Brazil.
Abstract:
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.
Insights
Hepatitis C virus (HCV) entry inhibitors are crucial for developing new treatments, as current direct-acting antivirals (DAAs) are not effective for everyone. This review highlights promising compounds targeting HCV entry, including ITX 5061 and chlorcyclizine.
Area of Science:
- Virology
- Hepatology
- Drug Discovery
Background:
- Hepatitis C virus (HCV) infection impacts 70 million globally, causing severe liver disease and hepatocellular carcinoma.
- Despite direct-acting antivirals (DAAs), 5-10% of patients do not clear the virus, and no vaccine exists.
- Virus entry is a critical target for developing novel antiviral strategies against HCV.
Approach:
- This review focuses on inhibitors targeting the Hepatitis C virus entry mechanism.
- It discusses structure-activity relationship (SAR) analyses of promising compounds.
- Recent advancements and contributions in the field of HCV entry inhibition are explored.
Key Points:
- ITX 5061, a sterol-regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) inhibitor, shows high efficacy (EC50: 0.25 nM) and completed Phase I trials.
- Chlorcyclizine demonstrates dual activity, inhibiting E1 apolipoproteins and NPC1L1 (EC50: 0.0331 μM, IC50: 2.3 nM).
- These compounds represent promising therapeutic leads for multi-target approaches, potentially combined with DAAs.
Conclusions:
- Targeting HCV entry presents a viable strategy for developing new antiviral therapies.
- ITX 5061 and chlorcyclizine are notable examples of effective entry inhibitors.
- Further research into these inhibitors and their SAR can advance HCV treatment.
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