Identification of novel small molecule inhibitors against the NS3/4A protease of hepatitis C virus genotype 4a

Author(s): Sara M. El-Sayed, Mohamed A.M. Ali*, Bahaa El-Dien M. El- Gendy, Samar S. Dandash, Yvette Issac, Reda Saad, Mohamed M. Azab, Mohamed R. Mohamed.

Journal Name: Current Pharmaceutical Design

Volume 24 , Issue 37 , 2018

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Abstract:

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.

Keywords: Hepatitis C virus, computer-designed chemically-synthesized compounds, direct-acting antiviral agents, NS3/4A protease inhibitors, pegylated interferon-alpha, chronic HCV infection.

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Article Details

VOLUME: 24
ISSUE: 37
Year: 2018
Page: [4484 - 4491]
Pages: 8
DOI: 10.2174/1381612825666181203153835
Price: $58

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