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

Autor(es)

de Moraes, Leonardo Nazario ^[1] ; Tommasini Grotto, Rejane Maria ^{[2, 1]} ; Valente, Guilherme Targino ^{[1, 3]} ; Sampaio, Heloisa de Carvalho ^[2] ; Magro, Angelo Jose ^{[2, 1, 4]} ; Fogaca, Lauana ^{[1, 4]} ; Wolf, Ivan Rodrigo ^[4] ; Perahia, David ^[5] ; Silva, Giovanni Faria ^[2] ; Simoes, Rafael Plana ^{[2, 1]}

Afiliação do(s) autor(es)

^[1] Sao Paulo State Univ, Sch Agr, Dept Bioproc & Biotechnol, UNESP, Ave Univ 3780, Botucatu, SP - Brazil

^[2] Sao Paulo State Univ, Blood Ctr, Med Sch, UNESP, Ave Prof Mario Rubens Guimaraes Montenegro S-N, Botucatu, SP - Brazil

^[3] Max Planck Inst Heart & Lung Res, Ludwigstr 43, D-61231 Bad Nauheim - Germany

^[4] Sao Paulo State Univ, Inst Biosci, UNESP, St Prof Dr Antonio Celso Wagner Zanin 250, Botucatu, SP - Brazil

^[5] Ecole Normale Super Paris Saclay, Lab Biol & Appl Pharmacol, F-94235 Cachan - France

• Tipo de documento: Artigo Científico
• Fonte: VIRUS RESEARCH; v. 274, DEC 2019.
• Citações Web of Science: 0

Resumo

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: D168N and L1531. The substitution D168N 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 L1531 mutation, the resistance mechanism is different from previous models reported in the literature. The L1531 substitution decreases the S139 deprotonation susceptibility, and consequently, this mutation impairs the covalent binding between the residue 5139 from NS3 and the electrophilic trap on boceprevir, which can induce drug failure. These results were supported by the time course analysis of the mutations of the NS3 protease, which showed that boceprevir was designed for enzymes with an L residue at position 153; however, the sequences with 1153 are predominant nowadays. The results presented here could be used to infer about resistance in others DAA, mainly protease inhibitors. (AU)

• Processo FAPESP: 13/21214-9 - Avaliação de polimorfismos genéticos na progressão da infecção de pacientes monoinfectados e coinfectados com os vírus da imunodeficiência humana (HIV) e vírus da hepatite C (VHC)
• Beneficiário: Rejane Maria Tommasini Grotto
• Modalidade de apoio: Auxílio à Pesquisa - Regular