Discovery of SCH446211 (SCH6):  A New Ketoamide Inhibitor of the HCV NS3 Serine Protease and HCV Subgenomic RNA Replication

Bogen, Stéphane; Arasappan, Ashok; Bennett, Frank; Chen, Kevin; Jao, Edwin; Liu, Yi‐Tsung; Lovey, Raymond G.; Venkatraman, Srikanth; Pan, Weidong; Parekh, Tajel; Pike, Russel; Ruan, Sumei; Liu, Rong; Baroudy, Bahige M.; Agrawal, Sony; Chase, Robert A.; Ingravallo, Paul; Pichardo, John; Prongay, Andrew; Brisson, Jean-Marc; Hsieh, Tony Y.; Cheng, Kui; Kemp, Scott J.; Levy, Odile E.; Lim-Wilby, Marguerita S.L.; Tamura, Shigeki; Saksena, Anil K.; Girijavallabhan, Viyyoor; Njoroge, F. George

doi:10.1021/jm060077j

Cited by 55 publications

(61 citation statements)

References 30 publications

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“…However, they may be difficult to depict, based solely on sequence examination, if, similarly to TRIF and CARDIF, they diverge from the consensus NS3/4A cleavage sequence. The highly specific productbased macrocyclic NS3 protease inhibitor BILN 2061 [74] and the less toxic new generation of another class of NS3 inhibitors, referred to as electrophilic or serine-trap inhibitors, such as VX-950 [75] and SCH6 [76] , probably exert their high inhibitory effect on HCV infection, not only by preventing HCV expression [77] but also by preventing NS3/4A to interfere with IFN induction.…”

Section: Ifn Inducing Pathwaysmentioning

confidence: 99%

The interferon inducing pathways and the hepatitis C virus

Meurs

Breiman

2007

WJG

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The innate immune response is triggered by a variety of pathogens, including viruses, and requires rapid induction of type I interferons (IFN), such as IFNβ and IFNα. IFN induction occurs when specific pathogen motifs bind to specific cellular receptors. In non-professional immune, virally-infected cells, IFN induction is essentially initiated after the binding of dsRNA structures to TLR3 receptors or to intracytosolic RNA helicases, such as RIG-I /MDA5. This leads to the recruitment of specific adaptors, such as TRIF for TLR3 and the mitochondrial-associated IPS-1/VISA/MAVS/CARDIF adapter protein for the RNA helicases, and the ultimate recruitment of kinases, such as MAPKs, the canonical IKK complex and the TBK1/IKKε kinases, which activate the transcription factors ATF-2/ c-jun, NF-κB and IRF3, respectively. The coordinated action of these transcription factors leads to induction of IFN and of pro-inflammatory cytokines and to the establishment of the innate immune response. HCV can cleave both the adapters TRIF and IPS-1/VISA/MAVS/ CARDIF through the action of its NS3/4A protease. This provokes abrogation of the induction of the IFN and cytokine pathways and favours viral propagation and presumably HCV chronic infection.

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Section: Ifn Inducing Pathwaysmentioning

confidence: 99%

The interferon inducing pathways and the hepatitis C virus

Meurs

Breiman

2007

WJG

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“…The P2 benzene ring has been macrocyclized with the P3 capping group through an aryl-alkyl ether linkage to depeptize the P2-P3 moiety [28]. These are the conformationally preorganized inhibitors with better stability and strong potency [28][29][30]. Recently, a series of potent tripeptide truncated at the N-terminus from some hexapeptide ketoacid inhibitors are described to explore the P2-P3 binding features [31].…”

Section: Introductionmentioning

confidence: 99%

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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“…6,7 Several NS3/4 protease protease inhibitors (PIs) have been developed to block this step of the viral life cycle and have been proved, in some cases, to significantly decrease the plasma viral load of infected individuals. [8][9][10][11] Since the first description of HCV, numerous studies have described the HCV variability found in infected individuals. 12,13 The observed HCV heterogeneity, like other RNA viruses, originates from the high rate of incorrect nucleotide substitutions during viral RNA replication (10 Ϫ4 -10 Ϫ5 mutations per nucleotide and per replication cycle) 14 and rapid viral turnover (producing on average 10 12 virions per day in infected individuals).…”

mentioning

confidence: 99%

Genetic and catalytic efficiency structure of an HCV protease quasispecies†

Franco¹,

Parera²,

Aparicio³

et al. 2007

Hepatology

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The HCV nonstructural protein (NS)3/4A serine protease is not only involved in viral polyprotein processing but also efficiently blocks the retinoic-acid-inducible gen I and Toll-like receptor 3 signaling pathways and contributes to virus persistence by enabling HCV to escape the interferon antiviral response. Therefore, the NS3/4A protease has emerged as an ideal target for the control of the disease and the development of new anti-HCV agents. Here, we analyzed, at a high resolution (approximately 100 individual clones), the HCV NS3 protease gene quasispecies from three infected individuals. Nucleotide heterogeneity of 49%, 84%, and 91% were identified, respectively, which created a dense net that linked different parts of the viral population. Minority variants having mutations involved in the acquisition of resistance to current NS3/4A protease inhibitors (PIs) were also found. A vast diversity of different catalytic efficiencies could be distinguished. Importantly, 67% of the analyzed enzymes displayed a detectable protease activity. Moreover, 35% of the minority individual variants showed similar or better catalytic efficiency than the master (most abundant) enzyme. Nevertheless, and in contrast to minority variants, master enzymes always displayed a high catalytic efficiency when different viral polyprotein cleavage sites were tested. Finally, genetic and catalytic efficiency differences were observed when the 3 quasispecies were compared, suggesting that different selective forces were acting in different infected individuals. Conclusion: The rugged HCV protease quasispecies landscape should be able to react to environmental changes that may threaten its survival. (HEPATOLOGY 2007;45:899-910.)

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Discovery of SCH446211 (SCH6): A New Ketoamide Inhibitor of the HCV NS3 Serine Protease and HCV Subgenomic RNA Replication

Cited by 55 publications

References 30 publications

The interferon inducing pathways and the hepatitis C virus

The interferon inducing pathways and the hepatitis C virus

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

Genetic and catalytic efficiency structure of an HCV protease quasispecies†

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