Adel El-Sokkary, Mohamed M. Gotina, Lizaveta Al-Sanea, Mohammad M. Pae, Ae Nim Elbargisy, Rehab Mohammed 2024-01-19T16:04:05Z 2024-01-19T16:04:05Z 2022-01-25 2020-11 1178-6973 https://pubs.kist.re.kr/handle/201004/117870 Background: 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. English Dove Medical Press Ltd Molecular Characterization of Hepatitis C Virus for Developed Antiviral Agents Resistance Mutations and New Insights into in-silico Prediction Studies Article 10.2147/IDR.S267809 1 Infection and Drug Resistance, v.13, pp.4235 - 4248 Infection and Drug Resistance 13 4235 4248 Y scie scopus 000615262100006 2-s2.0-85098251972 Infectious Diseases Pharmacology & Pharmacy Infectious Diseases Pharmacology & Pharmacy Article PLUS RIBAVIRIN POLYMERASE EPIDEMIOLOGY REPLICATION VARIABILITY SOFOSBUVIR INHIBITOR CORRELATE EGYPT S282 hepatitis C virus drug resistance T282S mutation direct-acting antivirals molecular docking