In vitro antiviral activity of SCH446211 (SCH6), a novel inhibitor of the hepatitis C virus NS3 serine protease - PubMed
doi: 10.1093/jac/dkl455. Epub 2006 Dec 5.
Karim Abid, John Pichardo, Valerio Pazienza, Paul Ingravallo, Rong Kong, Sony Agrawal, Stephane Bogen, Anil Saksena, Kuo-Chi Cheng, Andrew Prongay, F George Njoroge, Bahige M Baroudy, Francesco Negro
Affiliations
- PMID: 17151003
- DOI: 10.1093/jac/dkl455
In vitro antiviral activity of SCH446211 (SCH6), a novel inhibitor of the hepatitis C virus NS3 serine protease
Rong Liu et al. J Antimicrob Chemother. 2007 Jan.
Abstract
Background: Current hepatitis C virus (HCV) therapies may cure approximately 60% of infections. They are often contraindicated or poorly tolerated, underscoring the need for safer and more effective drugs. A novel, alpha-ketoamide-derived, substrate-based inhibitor of the HCV serine protease (SCH446211) was developed. Compared with earlier reported inhibitors of similar chemical class, it has a P1'-P2' extension which provides extended interaction with the protease active site. The aim of this study was to evaluate the in vitro antiviral activity of SCH446211.
Methods: Binding constant of SCH446211 to HCV NS3 protease was measured with the chromogenic substrate in vitro cleavage assay. Cell-based activity of SCH446211 was evaluated in replicon cells, which are Huh-7 hepatoma cells stably transfected with a subgenomic HCV RNA as reported previously. After 72 h of incubation with SCH446211, viral transcription and protein expression were measured by real-time RT-PCR (TaqMan), quantitative in situ hybridization, immunoblot and indirect immunofluorescence.
Results: The binding constant of SCH446211 to HCV NS3 protease was 3.8 +/- 0.4 nM. HCV replication and protein expression were inhibited by SCH446211 in replicon cells as consistently shown by four techniques. In particular, based on quantitative real-time RT-PCR measurements, the IC50 and IC90 of SCH446211 were estimated to be 40 +/- 20 and 100 +/- 20 nM (n = 17), respectively. Long-term culture of replicon cells with SCH446211 reduced replicon RNA to <0.1 copy per cell. SCH446211 did not show cellular toxicity at concentrations up to 50 microM.
Conclusions: SCH446211 is a potent inhibitor of HCV protease in vitro. Its extended interaction with the HCV NS3 protease active site is associated with potent in vitro antiviral activity. This observation is potentially a useful guide for development of future potent inhibitors against HCV NS3 protease.
Similar articles
-
Bogen SL, Arasappan A, Bennett F, Chen K, Jao E, Liu YT, Lovey RG, Venkatraman S, Pan W, Parekh T, Pike RE, Ruan S, Liu R, Baroudy B, Agrawal S, Chase R, Ingravallo P, Pichardo J, Prongay A, Brisson JM, Hsieh TY, Cheng KC, Kemp SJ, Levy OE, Lim-Wilby M, Tamura SY, Saksena AK, Girijavallabhan V, Njoroge FG. Bogen SL, et al. J Med Chem. 2006 May 4;49(9):2750-7. doi: 10.1021/jm060077j. J Med Chem. 2006. PMID: 16640336
-
Horscroft N, Bellows D, Ansari I, Lai VC, Dempsey S, Liang D, Donis R, Zhong W, Hong Z. Horscroft N, et al. J Virol. 2005 Mar;79(5):2788-96. doi: 10.1128/JVI.79.5.2788-2796.2005. J Virol. 2005. PMID: 15708997 Free PMC article.
-
Njoroge FG, Chen KX, Shih NY, Piwinski JJ. Njoroge FG, et al. Acc Chem Res. 2008 Jan;41(1):50-9. doi: 10.1021/ar700109k. Acc Chem Res. 2008. PMID: 18193821 Review.
-
Inhibition of hepatitis C virus RNA replicons by peptide aptamers.
Trahtenherts A, Gal-Tanamy M, Zemel R, Bachmatov L, Loewenstein S, Tur-Kaspa R, Benhar I. Trahtenherts A, et al. Antiviral Res. 2008 Mar;77(3):195-205. doi: 10.1016/j.antiviral.2007.12.013. Epub 2008 Jan 22. Antiviral Res. 2008. PMID: 18243349
-
A review of HCV protease inhibitors.
Chen KX, Njoroge FG. Chen KX, et al. Curr Opin Investig Drugs. 2009 Aug;10(8):821-37. Curr Opin Investig Drugs. 2009. PMID: 19649927 Review.
Cited by
-
Organic carbamates in drug design and medicinal chemistry.
Ghosh AK, Brindisi M. Ghosh AK, et al. J Med Chem. 2015 Apr 9;58(7):2895-940. doi: 10.1021/jm501371s. Epub 2015 Jan 7. J Med Chem. 2015. PMID: 25565044 Free PMC article. Review.
-
Jiang M, Mani N, Lin C, Ardzinski A, Nelson M, Reagan D, Bartels D, Zhou Y, Nicolas O, Rao BG, Müh U, Hanzelka B, Tigges A, Rijnbrand R, Kieffer TL. Jiang M, et al. Antimicrob Agents Chemother. 2013 Dec;57(12):6236-45. doi: 10.1128/AAC.01578-13. Epub 2013 Oct 7. Antimicrob Agents Chemother. 2013. PMID: 24100495 Free PMC article.
-
Naturally occurring mutations to HCV protease inhibitors in treatment-naïve patients.
Paolucci S, Fiorina L, Piralla A, Gulminetti R, Novati S, Barbarini G, Sacchi P, Gatti M, Dossena L, Baldanti F. Paolucci S, et al. Virol J. 2012 Oct 24;9:245. doi: 10.1186/1743-422X-9-245. Virol J. 2012. PMID: 23095680 Free PMC article.
-
Hepatitis viruses exploitation of host DNA methyltransferases functions.
Pazienza V, Panebianco C, Andriulli A. Pazienza V, et al. Clin Exp Med. 2016 Aug;16(3):265-72. doi: 10.1007/s10238-015-0372-3. Epub 2015 Jul 7. Clin Exp Med. 2016. PMID: 26148656 Review.
-
Modulation of host metabolism as a target of new antivirals.
Ikeda M, Kato N. Ikeda M, et al. Adv Drug Deliv Rev. 2007 Oct 10;59(12):1277-89. doi: 10.1016/j.addr.2007.03.021. Epub 2007 Aug 11. Adv Drug Deliv Rev. 2007. PMID: 17897752 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources