PMID- 23629699
OWN - NLM
STAT- MEDLINE
DCOM- 20131231
LR  - 20211021
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 57
IP  - 7
DP  - 2013 Jul
TI  - Identification of PTC725, an orally bioavailable small molecule that selectively 
      targets the hepatitis C Virus NS4B protein.
PG  - 3250-61
LID - 10.1128/AAC.00527-13 [doi]
AB  - 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.
FAU - Gu, Zhengxian
AU  - Gu Z
AD  - PTC Therapeutics, Inc., South Plainfield, New Jersey, USA.
FAU - Graci, Jason D
AU  - Graci JD
FAU - Lahser, Frederick C
AU  - Lahser FC
FAU - Breslin, Jamie J
AU  - Breslin JJ
FAU - Jung, Stephen P
AU  - Jung SP
FAU - Crona, James H
AU  - Crona JH
FAU - McMonagle, Patricia
AU  - McMonagle P
FAU - Xia, Ellen
AU  - Xia E
FAU - Liu, Shaotang
AU  - Liu S
FAU - Karp, Gary
AU  - Karp G
FAU - Zhu, Jin
AU  - Zhu J
FAU - Huang, Song
AU  - Huang S
FAU - Nomeir, Amin
AU  - Nomeir A
FAU - Weetall, Marla
AU  - Weetall M
FAU - Almstead, Neil G
AU  - Almstead NG
FAU - Peltz, Stuart W
AU  - Peltz SW
FAU - Tong, Xiao
AU  - Tong X
FAU - Ralston, Robert
AU  - Ralston R
FAU - Colacino, Joseph M
AU  - Colacino JM
LA  - eng
PT  - Journal Article
DEP - 20130429
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 
      (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)
RN  - 0 (Antiviral Agents)
RN  - 0 (Indoles)
RN  - 0 (Interferon-alpha)
RN  - 0 (NS4B protein, flavivirus)
RN  - 0 (Sulfonamides)
RN  - 0 (Viral Nonstructural Proteins)
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - Antiviral Agents/*metabolism/pharmacokinetics/*pharmacology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Viral/genetics
MH  - Drug Synergism
MH  - Hepacivirus/*drug effects
MH  - Hepatitis C/*drug therapy
MH  - Humans
MH  - Indoles/metabolism/pharmacokinetics/*pharmacology
MH  - Interferon-alpha/pharmacology
MH  - Male
MH  - Mice
MH  - Microbial Sensitivity Tests
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sulfonamides/metabolism/pharmacokinetics/*pharmacology
MH  - Viral Nonstructural Proteins/genetics/*metabolism
MH  - Virus Replication/drug effects
PMC - PMC3697315
EDAT- 2013/05/01 06:00
MHDA- 2014/01/01 06:00
PMCR- 2013/07/01
CRDT- 2013/05/01 06:00
PHST- 2013/05/01 06:00 [entrez]
PHST- 2013/05/01 06:00 [pubmed]
PHST- 2014/01/01 06:00 [medline]
PHST- 2013/07/01 00:00 [pmc-release]
AID - AAC.00527-13 [pii]
AID - 00527-13 [pii]
AID - 10.1128/AAC.00527-13 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2013 Jul;57(7):3250-61. doi: 10.1128/AAC.00527-13. 
      Epub 2013 Apr 29.