Background: Hepatitis C virus (HCV) infection poses a considerable threat to the public health. The
current standard of care treatment with pegylated interferon-alpha in combination with ribavirin (PEG-IFN-
α+RBV) is associated with significant side effects, poorly tolerated, and provides limited efficacy. The development
of direct-acting antiviral agents (DAAs) targeting key viral enzymes essential for viral replication represents
a significant milestone in the treatment of chronic HCV infection. Given its critical role in the viral polyprotein
processing and the evasion of the host innate immunity, the NS3/4A protease has emerged as a promising drug
target for the development of anti-HCV therapies. Although several potent NS3/4A protease inhibitors (PIs) have
been approved or are in clinical development, the majority of currently available PIs have significant limitations
related to untoward adverse events and a lack of pan-genotypic activity, indicating a continuing unmet medical
need for the development and optimization of novel PIs with improved efficacy and tolerability, convenient dosing
schedules, and shorter treatment durations.
Methods: The inhibitory efficacy of four computer-designed chemically-synthesized compounds was evaluated
against in vitro-expressed NS3/4A protease from HCV genotype 4a, the most prevalent genotype in Egypt, using
a fluorescence-based enzymatic assay.
Results: We successfully identified two non-macrocyclic small molecules, BE113 (7a) and BE114 (7b), which
exhibited inhibitory activity against HCV NS3/4A protease from HCV genotype 4a.
Conclusion: The two compounds presented in this study may be promising inhibitors against NS3/4A protease of
HCV genotype 4a and could be novel lead compounds for developing new therapeutics for the treatment of
chronic HCV infection.