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Resumen: The nonstructural protein 3 (NS3) from the hepatitis C virus processes the non-structural region of the viral precursor polyprotein in infected hepatic cells. The NS3 protease activity has been considered a target for drug development since its identification two decades ago. Although specific inhibitors have been approved for clinical therapy very recently, resistance-associated mutations have already been reported for those drugs, compromising their long-term efficacy. Therefore, there is an urgent need for new anti-HCV agents with low susceptibility to resistance-associated mutations. Regarding NS3 protease, two strategies have been followed: competitive inhibitors blocking the active site and allosteric inhibitors blocking the binding of the accessory viral protein NS4A. In this work we exploit the intrinsic Zn+2-regulated plasticity of the protease to identify a new type of allosteric inhibitors. In the absence of Zn+2, the NS3 protease adopts a partially-folded inactive conformation. We found ligands binding to the Zn+2-free NS3 protease, trap the inactive protein, and block the viral life cycle. The efficacy of these compounds has been confirmed in replicon cell assays. Importantly, direct calorimetric assays reveal a low impact of known resistance-associated mutations, and enzymatic assays provide a direct evidence of their inhibitory activity. They constitute new low molecular-weight scaffolds for further optimization and provide several advantages: 1) new inhibition mechanism simultaneously blocking substrate and cofactor interactions in a non-competitive fashion, appropriate for combination therapy; 2) low impact of known resistance-associated mutations; 3) inhibition of NS4A binding, thus blocking its several effects on NS3 protease.
Idioma: Inglés
DOI: 10.1371/journal.pone.0069773
Año: 2013
Publicado en: PLoS One 8, 7 (2013), e69773 [10 pp]
ISSN: 1932-6203
Factor impacto JCR: 3.534 (2013)
Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 8 / 56 = 0.143 (2013) - Q1 - T1
Financiación: info:eu-repo/grantAgreement/ES/DGA/B01
Financiación: info:eu-repo/grantAgreement/ES/DGA/B89
Financiación: info:eu-repo/grantAgreement/ES/DGA/PI044-09
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI10-00186
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2010-16297
Financiación: info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19451
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PTA2009-2341-I
Financiación: info:eu-repo/grantAgreement/ES/UZ/UZ2009-BIO-05
Tipo y forma: Article (Published version)
Área (Departamento): Bioquímica y Biología Molecular (Departamento de Bioquímica y Biología Molecular y Celular)

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Articles > Artículos por área > Bioquímica y Biología Molecular