title: Identification of PTC725, an orally bioavailable small molecule that selectively targets the hepatitis C Virus NS4B protein.
abstract: 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 (EC50) of 1.7 nM and an EC90 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.
authors: PTC Therapeutics, Inc., South Plainfield, New Jersey, USA.
authors: Zhengxian
authors: Z
authors: Gu
authors: Jason D
authors: JD
authors: Graci
authors: Frederick C
authors: FC
authors: Lahser
authors: Jamie J
authors: JJ
authors: Breslin
authors: Stephen P
authors: SP
authors: Jung
authors: James H
authors: JH
authors: Crona
authors: Patricia
authors: P
authors: McMonagle
authors: Ellen
authors: E
authors: Xia
authors: Shaotang
authors: S
authors: Liu
authors: Gary
authors: G
authors: Karp
authors: Jin
authors: J
authors: Zhu
authors: Song
authors: S
authors: Huang
authors: Amin
authors: A
authors: Nomeir
authors: Marla
authors: M
authors: Weetall
authors: Neil G
authors: NG
authors: Almstead
authors: Stuart W
authors: SW
authors: Peltz
authors: Xiao
authors: X
authors: Tong
authors: Robert
authors: R
authors: Ralston
authors: Joseph M
authors: JM
authors: Colacino
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral / Q000235:genetics; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C585352:6-(3-cyano-6-ethyl-5-fluoro-1-(pyrimidin-2-yl)-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide; D000998:Antiviral Agents; D007211:Indoles; D016898:Interferon-alpha; C080107:NS4B protein, flavivirus; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins
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