Hepatitis C virus NS3-4A serine protease inhibitors: SAR of moiety with improved potency

Arasappan, Ashok; Njoroge, F. George; Chan, Tze‐Ming; Bennett, Frank; Bogen, Stéphane; Chen, K.; Gu, Haifeng; Hong, Liu Zhen; Jao, Edwin; Liu, Y.T.; Lovey, Raymond G.; Parekh, Tejal N.; Pike, Russel; Pinto, Patrick; Santhanam, B.; Venkatraman, Srikanth; Vaccaro, Henry; Wang, H.; Yang, Xiaozheng; Zhu, Ziqiang; McKittrick, Brian A.; Saksena, Anil K.; Girijavallabhan, Viyyoor; Pichardo, John; Butkiewicz, Nancy; Ingram, Richard; Malcolm, Bruce A.; Prongay, Andrew; Yao, Nanhua; Marten, B.; Madison, Vincent; Kemp, Scott J.; Levy, Odile E.; Lim-Wilby, Marguerita S.L.; Tamura, Shigeki; Ganguly, Ashit K.

doi:10.1016/j.bmcl.2005.06.091

Cited by 27 publications

(23 citation statements)

References 20 publications

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“…4a) of position P3 of the Hypo1 hypothesis. The backbone HD and NEG features of inhibitor 43 of K Ã i 0.066 mM measured and characterized by a cyclohexyglycine at P3, a leucine at P2, and a phenyl glycine at P2' position [46] is also mapped correctly onto the corresponding P3 features of Hypo1 hypothesis (Fig. 4b).…”

Section: (C) the Comsia H-bond Contours (Cyan Contours Favor H-bondmentioning

confidence: 97%

Exploring the P2 and P3 ligand binding features for Hepatitis C virus NS3 protease using some 3D QSAR techniques

Wei

Lin

2008

Journal of Molecular Graphics and Modelling

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Section: (C) the Comsia H-bond Contours (Cyan Contours Favor H-bondmentioning

confidence: 97%

Exploring the P2 and P3 ligand binding features for Hepatitis C virus NS3 protease using some 3D QSAR techniques

Wei

Lin

2008

Journal of Molecular Graphics and Modelling

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“…The x-ray structure of the NS3 protease-SCH6 complex was obtained as described previously (28). Point mutations were modeled into the three-dimensional structures using the InsightII molecular modeling program (Accelrys Software Inc., San Diego).…”

Section: Ns3/4a Protease Disruption Of Irf-3mentioning

confidence: 99%

Mutations Conferring Resistance to SCH6, a Novel Hepatitis C Virus NS3/4A Protease Inhibitor

Tong²,

Skelton³

et al. 2006

Journal of Biological Chemistry

100

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Drug resistance is a major issue in the development and use of specific antiviral therapies. Here we report the isolation and characterization of hepatitis C virus RNA replicons resistant to a novel ketoamide inhibitor of the NS3/4A protease, SCH6 (originally SCH446211). Resistant replicon RNAs were generated by G418 selection in the presence of SCH6 in a dose-dependent fashion, with the emergence of resistance reduced at higher SCH6 concentrations. Sequencing demonstrated remarkable consistency in the mutations conferring SCH6 resistance in genotype 1b replicons derived from two different strains of hepatitis C virus, A156T/ A156V and R109K. R109K, a novel mutation not reported previously to cause resistance to NS3/4A inhibitors, conferred moderate resistance only to SCH6. Structural analysis indicated that this reflects unique interactions of SCH6 with P-side residues in the protease active site. In contrast, A156T conferred high level resistance to SCH6 and a related ketoamide, SCH503034, as well as BILN 2061 and VX-950. Unlike R109K, which had minimal impact on NS3/4A enzymatic function, A156T significantly reduced NS3/4A catalytic efficiency, polyprotein processing, and replicon fitness. However, three separate second-site mutations, P89L, Q86R, and G162R, were capable of partially reversing A156T-associated defects in polyprotein processing and/or replicon fitness, without significantly reducing resistance to the protease inhibitor.

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“…The cyclohexyl moiety at P 3 provided additional hydrophobic contacts in comparison with smaller groups at P 3 . 8 The P 1 -P 0 2 residues form a ÔC-clampÕ that wraps over the side chain of lys136.…”

Section: Targets Included Inmentioning

confidence: 99%

“…1). 8 From the X-ray crystal structure of compound 1 bound to the protease, it was evident that the P 1 -P 0 2 side chains formed a C-clamp around Lys136 of the protease and thus provided extensive hydrophobic interaction that resulted in improved potency. X-ray crystal structure analysis also revealed a close proximity of P 2 side chain to arginine 155.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus NS3-4A serine protease inhibitors: Use of a P2–P1 cyclopropyl alanine combination for improved potency

Bogen¹,

Saksena²,

Arasappan³

et al. 2005

Bioorganic & Medicinal Chemistry Letters

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Hepatitis C virus NS3-4A serine protease inhibitors: SAR of moiety with improved potency

Cited by 27 publications

References 20 publications

Exploring the P2 and P3 ligand binding features for Hepatitis C virus NS3 protease using some 3D QSAR techniques

Exploring the P2 and P3 ligand binding features for Hepatitis C virus NS3 protease using some 3D QSAR techniques

Mutations Conferring Resistance to SCH6, a Novel Hepatitis C Virus NS3/4A Protease Inhibitor

Hepatitis C virus NS3-4A serine protease inhibitors: Use of a P2–P1 cyclopropyl alanine combination for improved potency

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