BACKGROUND/AIMS: One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutations in the HCV protease (R155Q, A156T, D168A and D168V) have been identified in vitro in the HCV replicon system that confer resistance to BILN-2061 (a reference inhibitor). However, the molecular mechanism of drug resistance is still unknown. The aim of this study is to unravel, using an molecular modelling strategy, the structural basis of such molecular mechanism of HCV resistance to PIs. We focused on protease mutations conferring HCV resistance to BILN-2061 and described for the first time such mechanism at a molecular level. METHODS: The structures of drug-resistant NS3 proteases were obtained by mutation of selected residues (R155Q, A156T, D168A and D168V) and the ternary complexes formed between NS3-4A and BILN-2061 were optimized using GenMol software (www.3dgenoscience.com; Genoscience, Marseille, France). RESULTS: Two mechanisms were evidenced for viral resistance to BILN-2061. A 'direct' resistance mechanism is based on contacts between the mutated R155Q and A156T protease residues and its inhibitor. In the 'indirect' resistance mechanism, the mutated D168A/V residue is not in close contact with the drug itself but interacts with other residues connected to the drug. CONCLUSIONS: These data provide new insights in the understanding of the mechanisms of HCV drug escape, and may allow predicting potential cross-resistance phenomenon with other PIs. This approach can be used as a basis for future rational PI drug design candidates.
BACKGROUND/AIMS: One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutations in the HCV protease (R155Q, A156T, D168A and D168V) have been identified in vitro in the HCV replicon system that confer resistance to BILN-2061 (a reference inhibitor). However, the molecular mechanism of drug resistance is still unknown. The aim of this study is to unravel, using an molecular modelling strategy, the structural basis of such molecular mechanism of HCV resistance to PIs. We focused on protease mutations conferring HCV resistance to BILN-2061 and described for the first time such mechanism at a molecular level. METHODS: The structures of drug-resistant NS3 proteases were obtained by mutation of selected residues (R155Q, A156T, D168A and D168V) and the ternary complexes formed between NS3-4A and BILN-2061 were optimized using GenMol software (www.3dgenoscience.com; Genoscience, Marseille, France). RESULTS: Two mechanisms were evidenced for viral resistance to BILN-2061. A 'direct' resistance mechanism is based on contacts between the mutated R155Q and A156T protease residues and its inhibitor. In the 'indirect' resistance mechanism, the mutated D168A/V residue is not in close contact with the drug itself but interacts with other residues connected to the drug. CONCLUSIONS: These data provide new insights in the understanding of the mechanisms of HCV drug escape, and may allow predicting potential cross-resistance phenomenon with other PIs. This approach can be used as a basis for future rational PI drug design candidates.
Authors: Feng Ni; Smitha Kota; Virginia Takahashi; A Donny Strosberg; John K Snyder Journal: Bioorg Med Chem Lett Date: 2011-04-15 Impact factor: 2.823
Authors: Anna K Lampa; Sara M Bergman; Sofia S Gustafsson; Hiba Alogheli; Eva B Akerblom; Gunnar G Lindeberg; Richard M Svensson; Per Artursson; U Helena Danielson; Anders Karlén; Anja Sandström Journal: ACS Med Chem Lett Date: 2013-08-02 Impact factor: 4.345
Authors: Wanguo Wei; Cuifang Cai; Smitha Kota; Virginia Takahashi; Feng Ni; A Donny Strosberg; John K Snyder Journal: Bioorg Med Chem Lett Date: 2009-10-21 Impact factor: 2.823
Authors: Smitha Kota; Louis Scampavia; Timothy Spicer; Aaron B Beeler; Virginia Takahashi; John K Snyder; John A Porco; Peter Hodder; Arthur Donny Strosberg Journal: Assay Drug Dev Technol Date: 2010-02 Impact factor: 1.738
Authors: Arthur Donny Strosberg; Smitha Kota; Virginia Takahashi; John K Snyder; Guillaume Mousseau Journal: Viruses Date: 2010-08-20 Impact factor: 5.818