Identification of PTC725, an orally bioavailable small molecule that selectively targets the hepatitis C Virus NS4B protein
| Autor: | Xiao Tong, Frederick C. Lahser, Stuart W. Peltz, Shaotang Liu, Patricia McMonagle, Song Huang, Stephen P. Jung, Jin Zhu, Jamie Breslin, Joseph M. Colacino, Neil Gregory Almstead, Gary Mitchell Karp, Robert Ralston, Jason D. Graci, Ellen Xia, Zhengxian Gu, Marla Weetall, Amin A. Nomeir, James H. Crona |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Indoles medicine.medical_treatment Hepatitis C virus viruses Alpha interferon Hepacivirus Microbial Sensitivity Tests Viral Nonstructural Proteins medicine.disease_cause Virus Replication Antiviral Agents Virus Rats Sprague-Dawley Mice Cell Line Tumor Drug Resistance Viral medicine Animals Humans Pharmacology (medical) Replicon NS5A Polymerase Pharmacology NS3 Sulfonamides Protease biology Interferon-alpha Drug Synergism Virology Hepatitis C Rats Infectious Diseases Amino Acid Substitution biology.protein |
| Zdroj: | Antimicrobial agents and chemotherapy. 57(7) |
| ISSN: | 1098-6596 |
| Popis: | While new direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection have been approved, there is a continued need for novel antiviral agents that act on new targets and can be used in combination with current therapies to enhance efficacy and to restrict the emergence of drug-resistant viral variants. To this end, we have identified a novel class of small molecules, exemplified by PTC725, that target the nonstructural protein 4B (NS4B). PTC725 inhibited HCV 1b (Con1) replicons with a 50% effective concentration (EC 50 ) of 1.7 nM and an EC 90 of 9.6 nM and demonstrated a >1,000-fold selectivity window with respect to cytotoxicity. The compounds were fully active against HCV replicon mutants that are resistant to inhibitors of NS3 protease and NS5B polymerase. Replicons selected for resistance to PTC725 harbored amino acid substitutions F98L/C and V105M in NS4B. Anti-replicon activity of PTC725 was additive to synergistic in combination with alpha interferon or with inhibitors of HCV protease and polymerase. Immunofluorescence microscopy demonstrated that neither the HCV inhibitors nor the F98C substitution altered the subcellular localization of NS4B or NS5A in replicon cells. Oral dosing of PTC725 showed a favorable pharmacokinetic profile with high liver and plasma exposure in mice and rats. Modeling of dosing regimens in humans indicates that a once-per-day or twice-per-day oral dosing regimen is feasible. Overall, the preclinical data support the development of PTC725 for use in the treatment of chronic HCV infection. |
| Databáze: | OpenAIRE |
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