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Mohamed M Adel El-Sokkary,1 Lizaveta Gotina,2,3 Mohammad M Al-Sanea,4 Ae Nim Pae,2,3 Rehab Mohammed Elbargisy1,5 1Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; 2Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 02792, Republic of Korea; 3Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Daejeon, Korea; 4Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia; 5Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi ArabiaCorrespondence: Mohamed M Adel El-SokkaryDepartment of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, EgyptEmail m_elsokkary2022@yahoo.comAe Nim PaeConvergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Hwarangno 14-Gil 5, Seongbuk-gu, Seoul 02792, Republic of KoreaEmail anpae@kist.re.krBackground: Identification and characterization of developed antiviral drug resistance mutations are key to the success of antiviral therapies against hepatitis C virus (HCV), which remains a worldwide highly prevalent pathogenic disease. Although most studies focus on HCV genotypes 1, 2 or 3, the investigation of drug resistance in HCV genotype 4, predominant in North Africa, is especially significant in Egypt.Methods: We performed mutational and genotypic analysis of the untranslated region (UTR) and nonstructural protein 5B (NS5B) drug resistance-associated regions of HCV for patients in the surrounding villages of Mansoura city, who were not responding to different antiviral treatments (sofosbuvir (SOF), ribavirin, and interferon). Furthermore, molecular modelling approaches (homology modelling and docking studies) were used to investigate the significance of the identified NS5B mutations for SOF and ribavirin binding in the HCV genotype 4a NS5B active site.Results: Genotypic analysis confirmed all samples to have genotype 4 with sub-genotype 4a predominant. Partial sequencing of the UTR and NS5B resistance-associated regions identified D258E, T282S and A307G mutations in all isolates of NS5B. The UTR mutation site at position 243 was associated with interferon resistance, whereas the NS5B T282S mutation was considered as significant for SOF and ribavirin resistance. Docking studies in the HCV genotype 4a homology model predict SOF and ribavirin to accommodate a nucleotide-like binding mode, in which the T282 residue does interfere with the binding as it would in HCV genotypes 1 and 2. Mutation energy calculations predict T282S to moderately destabilize the binding of SOF and ribavirin by 0.57 and 0.47 kcal/mol, respectively.Conclusion: The performed study identified and characterized several antiviral drug resistance mutations of HCV genotype 4a and proposed a mechanism by which the T282S mutation may contribute to SOF and ribavirin resistance.Keywords: hepatitis C virus, drug resistance, T282S mutation, direct-acting antivirals, molecular docking