7 Preclinical Characterization of Pro 206, an Orally Active Small-Molecule Hepatitis C (Hcv) Entry Inhibitor

Qian, Dapeng; Coburn, Glen A.; Han, Amy; Muys, J.-M. de; Gauss, Carla‐Maria; Provoncha, Kathleen; Canfield, M.; Paul, Dahrii; Mohamed, S. M.; Moorji, Sameer M.; Fisch, Danielle N.; Murga, Jose D.; Rotshteyn, Yakov; Maddon, Paul J.; Olson, William C.

doi:10.1016/s0168-8278(09)60009-x

Cited by 4 publications

(5 citation statements)

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“…Third, the virus selection approach makes it possible to identify resistance mutations for inhibitors that target steps other than replication (38). This will likely become increasingly important as antiviral strategies targeting HCV entry, assembly, NS2 or structural proteins emerge (21,25).…”

Section: Discussionmentioning

confidence: 99%

Selection of Clinically Relevant Protease Inhibitor-Resistant Viruses Using the Genotype 2a Hepatitis C Virus Infection System

Cheng

Chan

Yang

et al. 2011

Antimicrob Agents Chemother

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Treatment of patients infected with hepatitis C virus (HCV) with direct acting antivirals can lead to the emergence of drug-resistant variants that may pose a long-term threat to viral eradication. HCV replicons have been used to select resistance mutations; however, genotype 2a JFH-1-based viruses provide the opportunity to perform resistance selection in a bona fide infection system. In this study, we used a tissue culture-adapted J6/JFH-1 virus to select resistance to the NS3 protease inhibitors BILN-2061 and VX-950. Lunet-CD81 cells were infected with J6/JFH-1 virus and maintained in the presence of inhibitors until high-titer viral supernatant was produced. Viral supernatants were passaged over naive cells at escalating drug concentrations, and the resulting viruses were then characterized. Three NS3 resistance mutations were identified in BILN-2061-resistant viruses: A156G, D168A, and D168V. Interestingly, D168A, D168V, and A156T/V, but not A156G, were selected in parallel using a genotype 2a replicon. For VX-950, the T54A and A156S NS3 resistance mutations were identified in the virus selections, whereas only A156T/V emerged in genotype 2a replicon selections. Of note, VX-950 resistance mutations selected using the 2a virus (T54A and A156S) were also observed during VX-950 clinical studies in genotype 2 patients. We also performed viral fitness evaluations and determined that the mutations selected in the viral system did not confer marked reductions in virus production kinetics or peak titers. Overall, the HCV infection system is an efficient tool for drug resistance selections and has advantages for the rapid identification and characterization of clinically relevant resistance mutations.Chronic hepatitis C virus (HCV) infection represents a significant and immediate worldwide health burden (2, 40). Accordingly, tremendous resources have been directed toward discovering and developing novel therapies to treat HCV infection. Currently, a number of direct-acting antiviral agents (DAAs) are under clinical development (7,35,37). Various DAAs have been designed to target distinct HCV viral proteins (3, 4, 6), including NS3 protease, NS5A, and the NS5B RNA-dependent RNA polymerase. During short-term monotherapy studies in HCV-infected patients, many of these DAAs have elicited pronounced antiviral effects (e.g., Ն3 log HCV viral load reductions in as few as 3 days of treatment). However, even in these short-term studies the selection of viral resistance was apparent and thus poses a significant challenge to the long-term efficacy of these novel agents (6,11,32,35).The HCV replicon has been a useful in vitro tool for identifying and characterizing resistance mutations for multiple classes of DAAs (11,32,35). For example, the NS3 mutations R155K, A156T/V, and D168A/V were selected in replicons using the first clinically active NS3 protease inhibitor, BILN-2061 (a prototype noncovalent NS3 inhibitor) (16,19). Unfortunately, the resistance profile of BILN-2061 in the clinic has not been reported, making it imposs...

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Section: Discussionmentioning

confidence: 99%

Selection of Clinically Relevant Protease Inhibitor-Resistant Viruses Using the Genotype 2a Hepatitis C Virus Infection System

Cheng

Chan

Yang

et al. 2011

Antimicrob Agents Chemother

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“…Pro 206 and IFN-α-2a act in vitro (HCVcc) in an additive fashion. The development of Pro 206 has been stopped [ 11 ]. Second-generation lead compounds are in preclinical development [ 12 ].…”

Section: Small Molecule Inhibitors Of Hcv Replication In Developmentmentioning

confidence: 99%

Antiviral Therapy for Hepatitis C Virus: Beyond the Standard of Care

Coelmont

Neyts

2010

Viruses

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Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed.

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“…In particular, PRO 206 also showed favorable pharmacokinetics and oral bioavailability [77]. However, the molecular target of PRO 206 is not known, and the compound seems to be selective for genotype 1 HCV.…”

Section: Random Screening For Hcv Entry Inhibitorsmentioning

confidence: 99%

“…Progenics Pharmaceuticals, Inc. utilized a similar approach and identified compounds that exhibited potent inhibitory activity against both HCVpp and HCVcc. In particular, PRO 206 also showed favorable pharmacokinetics and oral bioavailability [ 77 ]. However, the molecular target of PRO 206 is not known, and the compound seems to be selective for genotype 1 HCV.…”

Section: Random Screening For Hcv Entry Inhibitorsmentioning

confidence: 99%

Targeting HCV Entry For Development of Therapeutics

Wong‐Staal

Syder

McKelvy

2010

Viruses

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Recent progress in defining the molecular mechanisms of Hepatitis C Virus (HCV) entry affords the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors would limit the expansion of the infected cell reservoir, and would complement the many replication inhibitors now under development. The current model for the pathway of entry involves the initial docking of the virus onto the cell surface through interactions of virion envelope and associated low density lipoproteins (LDL) with cell surface glycosaminoglycans and lipoprotein receptors, followed by more specific utilization with other hepatocyte membrane proteins: Scavenger Receptor Class B type 1 (SR-BI), CD81, Claudin 1 (CLDN1) and Occludin (OCLN). The use of blockers of these interactions, e.g. specific antibodies, suggests that inhibition of any one step in the entry pathway can inhibit infection. Despite this knowledge base, the tools for compound screening, HCV pseudoparticles (HCVpp) and cell culture virus (HCVcc), and the ability to adapt them to industrial use are only recently available and as a result drug discovery initiatives are in their infancy. Several therapies aiming at modulating the virus envelope to prevent host cell binding are in early clinical testing. The first test case for blocking a cellular co-receptor is an SR-BI modulator. ITX 5061, an orally active small molecule, targets SR-BI and has shown potent antiviral activity against HCVpp and HCVcc. ITX 5061 has exhibited good safety in previous clinical studies, and is being evaluated in the clinic in chronic HCV patients and patients undergoing liver transplantation. Entry inhibitors promise to be valuable players in the future development of curative therapy against HCV.

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7 Preclinical Characterization of Pro 206, an Orally Active Small-Molecule Hepatitis C (Hcv) Entry Inhibitor

Cited by 4 publications

References 0 publications

Selection of Clinically Relevant Protease Inhibitor-Resistant Viruses Using the Genotype 2a Hepatitis C Virus Infection System

Selection of Clinically Relevant Protease Inhibitor-Resistant Viruses Using the Genotype 2a Hepatitis C Virus Infection System

Antiviral Therapy for Hepatitis C Virus: Beyond the Standard of Care

Targeting HCV Entry For Development of Therapeutics

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