A novel molecular mechanism to explain mutations of the HCV protease associated with resistance against covalently bound inhibitors.

A novel molecular mechanism to explain mutations of the HCV protease associated with resistance against covalently bound inhibitors.
Virus Res. 2019 Oct 13;:197778
Authors: de Moraes LN, Tommasini Grotto RM, Targino Valente G, de Carvalho Sampaio H, Magro AJ, Fogaça L, Wolf IR, Perahia D, Faria Silva G, Plana Simões R
Abstract
NS3 is an important therapeutic target for direct-acting antiviral (DAA) drugs. However, many patients treated with DAAs have unsustained virologic response (UVR) due to the high mutation rate of HCV. The aim of this work was to shed some light on the puzzling molecular mechanisms of the virus's of patients who showed high viral loads even under treatment with DAA. Bioinformatics tools, molecular modelling analyses were employed to identify mutations associated with HCV resistance to boceprevir and possible structural features related to this phenomenon. We identified two mutations of NS3 that may be associated with HCV resistance: D168 N and L153I. The substitution D168 N was previously reported in the literature as related with drug failure. Additionally, we identified that its molecular resistance mechanism can be explained by the destabilization of receptor-ligand hydrogen bonds. For the L153I mutation, the resistance mechanism is different from previous models reported in the literature. The L153I substitution decreases the S139 deprotonation susceptibility, and consequently, this mutation impairs th...

Source: Virus Research - October 12, 2019 Category: Virology Authors: de Moraes LN, Tommasini Grotto RM, Targino Valente G, de Carvalho Sampaio H, Magro AJ, Fogaça L, Wolf IR, Perahia D, Faria Silva G, Plana Simões R Tags: Virus Res Source Type: research