Computer analysis of resistance mutations to HCV NS5A antivirals

Abstract

Background: Hepatitis C virus (HCV) is characterized by a high replication rate associated with a high rate of genetic errors because viral RNA polymerase lacks correction systems. It is therefore not surprising that mutations that occur naturally in the HCV genome in some cases coincide with positions involving amino acids responsible for resistance to direct-acting antivirals (DAAs). Thus, it is important to determine whether mutations produce conformational changes that interfere with drug-target binding to prevent potential therapeutic failures. To develop computational analysis of the mutations of resistance to DAAs in the NS5A gene to identify conformational change of the protein Methods & Materials: Resistance mutations to DAAs described in the literature were represented in the three-dimensional structure of domain I of the NS5A protein. We used the program PyMol (http://pymol.sourceforge.net). We also used the structure Con1 isolate of HCV-1b extracted from the database Protein DataBank (www.ebi.ac.uk/pdbsum), with code (3FQQ). Results: Resistance mutations have been described in the N-terminal region of domain I of NS5A at amino acid positions 23, 28, 30, 31, 32, 54, 58 and 93. The mutations associated with resistance to DAAs were found where the surfaces of the two monomers forming NS5A dimer I were contacted. Conclusion: The mutations associated with the analyzed resistance were located close to the binding site of daclatasvir (DCV), and ledipasvir (LDV), which would affect the drug-target binding and would have a possible impact on the treatment with DAAs.