Submit Manuscript  

Article Details


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

[ Vol. 24 , Issue. 37 ]

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 and Mohamed R. Mohamed   Pages 4484 - 4491 ( 8 )

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.

Affiliation:

Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Chemistry Department, Faculty of Science, Benha University, Benha, Chemistry Department, Faculty of Science, Benha University, Benha, Chemistry Department, Faculty of Science, Benha University, Benha, Chemistry Department, Faculty of Science, Benha University, Benha, Chemistry Department, Faculty of Science, Benha University, Benha, Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo



Read Full-Text article