Design, Synthesis and Antiviral Evaluation of 2′-C-Methyl Branched Guanosine Pronucleotides: The Discovery of IDX184, a Potent Liver-Targeted HCV Polymerase Inhibitor

References

• Ashfaq UA , JavedT, RehmanS, NawazZ, RiazuddinS. An overview of HCV molecular biology, replication and immune response. Virol. J.8, 161 (2011).
   PubMed Web of Science ®Google Scholar
• Scheel TKH , RiceCM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat. Med.19 (7), 837–849 (2013).
   PubMed Web of Science ®Google Scholar
• Thomas DL . Global control of hepatitis C: where challenge meets opportunity. Nat. Med.19 (7), 850–858 (2013).
   PubMed Web of Science ®Google Scholar
• Lim TR , TanBH, MutimerDJ. Evolution and emergence of a new era of antiviral treatment for chronic hepatitis C infection. Int. J. Antimicrob. Agents43 (1), 17–25 (2014).
   PubMed Web of Science ®Google Scholar
• Au JS , PockrosPJ. Novel therapeutic approaches for hepatitis C. Clin. Pharmacol. Ther.95 (1), 78–88 (2014).
   PubMed Web of Science ®Google Scholar
• Conteduca V , SansonnoD, RussiSet al. Therapy of chronic hepatitis C virus infection in the era of direct-acting and host-targeting antiviral agents. J. Infect.68 (1), 1–20 (2014).
   PubMed Web of Science ®Google Scholar
• Hayes CN , ChayamaK. Emerging treatments for chronic hepatitis C. J. Formos. Med. Assoc.114 (3), 204–215 (2015).
   PubMed Web of Science ®Google Scholar
• Gerber L , WelzelTM, ZeuzemS. New therapeutic strategies in HCV: polymerase inhibitors. Liver Int.33 (Suppl 1), 85–92 (2013).
   PubMedGoogle Scholar
• Soriano V , VispoE, de MendozaCet al. Hepatitis C therapy with HCV NS5B polymerase inhibitors. Expert Opin. Pharmacother.14 (9), 1161–1170 (2013).
   PubMed Web of Science ®Google Scholar
• Pockros PJ . Nucleoside/nucleotide analogue polymerase inhibitors in development. Clin. Liver Disease17 (1), 105–110 (2013).
   PubMed Web of Science ®Google Scholar
• Deval J , HuberM. Hepatitis C virus and its inhibitors: the polymerase as a target for nucleoside and nucleotide analogs. In : Cancer-Causing Viruses and their Inhibitors. GuptaSP ( Ed.). CRC Press, 41–84 (2014).
   Google Scholar
• Deval J , SymonsJA, BeigelmanL. Inhibition of viral RNA polymerases by nucleoside and nucleotide analogs: therapeutic applications against positive-strand RNA viruses beyond hepatitis C virus. Curr. Opin. Virol.9, 1–7 (2014).
   PubMed Web of Science ®Google Scholar
• Coats SJ , Garnier-AmblardEC, AmblardFet al. Chutes and ladders in hepatitis C nucleoside drug development. Antivir. Res.102, 119–147 (2014).
   PubMed Web of Science ®Google Scholar
• De Clercq E . Sofosbuvir in the current context of hepatitis C Treatment. J. Symptoms Signs.3 (3), 126–131 (2014).
   Google Scholar
• Kayali Z , SchmidtWN. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmacogenomics Person. Med.7, 387–398 (2014).
   PubMedGoogle Scholar
• Sofia MJ . Beyond sofosbuvir: what opportunity exists for a better nucleoside/nucleotide to treat hepatitis C?Antivir. Res.107, 119–124 (July 2014).
   PubMed Web of Science ®Google Scholar
• Sommadossi JP , LacollaP : WO2001090121 (2001).
   Google Scholar
• Sommadossi JP , LacollaP : WO2001092282 (2001).
   Google Scholar
• Benzaria S , BardiotD, BouissetTet al. 2′-C-Methyl branched pyrimidine ribonucleoside analogues: potent inhibitors of RNA virus replication. Antivir. Chem. Chemother.18 (4), 225–242 (2007).
   PubMedGoogle Scholar
• Pierra C , BenzariaS, AmadorAet al. NM283, an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine. Nucleosides Nucleotides Nucleic Acids24 (5–7), 767–770 (2005).
   PubMed Web of Science ®Google Scholar
• Pierra C , AmadorA, BenzariaSet al. Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine. J. Med. Chem.49 (22), 6614–6620 (2006).
   PubMed Web of Science ®Google Scholar
• Sommadossi JP , GosselinG, PierraCet al. O2008082602 (2008).
   Google Scholar
• Sommadossi JP , GosselinG, PierraCet al. WO2008082601 (2008).
   Google Scholar
• Cretton-Scott E , Hernandez-SantiagoB, LarssonMet al. WO2010014134 (2010).
   Google Scholar
• Buckwold VE , BeerBE, DonisRO. Bovine viral diarrhea virus as a surrogate model of hepatitis C virus for the evaluation of antiviral agents. Antivir. Res.60 (1), 1–15 (2003).
   PubMed Web of Science ®Google Scholar
• Migliaccio G , TomassiniJE, CarrollSSet al. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem.278 (49), 49164–49170 (2003).
   PubMed Web of Science ®Google Scholar
• Eldrup AB , AllersonCR, BennettCFet al. Structure–activity relationship of purine ribonucleosides for inhibition of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem.47 (9), 2283–2295 (2004).
   PubMed Web of Science ®Google Scholar
• Eldrup AB , PrhavcM, BrooksJet al. Structure–activity relationship of heterobase-modified 2′-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication. J. Med. Chem.47 (21), 5284–5297 (2004).
   PubMed Web of Science ®Google Scholar
• Clark JL , MasonJC, HolleckerLet al. Synthesis and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methyl purine nucleosides as inhibitors of hepatitis C virus RNA replication. Bioorg. Med. Chem. Lett.16 (6), 1712–1715 (2006).
   PubMed Web of Science ®Google Scholar
• McGuigan C , PerroneP, MadelaKet al. The phosphoramidate ProTide approach greatly enhances the activity of β-2′-C-methylguanosine against hepatitis C virus. Bioorg. Med. Chem. Lett.19 (15), 4316–4320 (2009).
   PubMed Web of Science ®Google Scholar
• Amblard F , FromentinE, DetorioMet al. Synthesis, antiviral activity, and stability of nucleoside analogs containing tricyclic bases. Eur. J. Med. Chem.44 (10), 3845–3851 (2009).
   PubMed Web of Science ®Google Scholar
• Olsen DB , EldrupAB, BartholomewLet al. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob. Agents Chemother.48 (10), 3944–3953 (2004).
   PubMed Web of Science ®Google Scholar
• Ray AS , HitchcockMJM. Metabolism of antiviral nucleosides and nucleotides. In : Antiviral Research. Strategy in Antiviral Drug Discovery. LaFeminaRL ( Ed.). ASM Press, Washington, DC, USA, 301–315 (2009).
   Google Scholar
• Pradere U , Garnier-AmblardEC, CoatsSJet al. Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem. Rev.114 (18), 9154–9218 (2014).
   PubMed Web of Science ®Google Scholar
• Hurwiotz SJ , SchinaziRF. Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors. Curr. Opin. HIV AIDS.8 (6), 555–564 (2013).
   Web of Science ®Google Scholar
• Sofia MJ . Nucleotide prodrugs for the treatment of HCV infection. In : Advances in Pharmacolology Antiviral Agents. De ClercqE ( Ed.). Academic Press, Burlington, MA, USA, 39–73 (2013).
   Google Scholar
• Peyrottes S , PerigaudC. Mononucleotide prodrug synthetic strategies. In : Chemical Synthesis of Nucleoside Analogues. MerinoP ( Ed.). John Wiley & Sons, Hoboken, NJ, USA, 229–261 (2013).
   Google Scholar
• Ray AS , HostetlerKY. Application of kinase bypass strategies to nucleoside antivirals. Antivir. Res.92 (2), 277–291 (2011).
   PubMed Web of Science ®Google Scholar
• Peterson LW , McKennaCE. Prodrug approaches to improving the oral absorption of antiviral nucleotide analogues. Expert Opin. Drug Deliv.6 (4), 405–420 (2009).
   PubMed Web of Science ®Google Scholar
• Hecker SJ , ErionMD. Prodrugs of phosphates and phosphonates. J. Med. Chem.51 (8), 2328–2345 (2008).
   PubMed Web of Science ®Google Scholar
• Poijarvi-Virta P , LonnbergH. Prodrug approaches of nucleotides and oligonucleotides. Curr. Med. Chem.13 (28), 3441–3465 (2006).
   PubMed Web of Science ®Google Scholar
• Khan SR , NowakB, PlunkettWet al. Bis(pivaloyloxymethyl) thymidine 5′-phosphate is a cell membrane-permeable precursor of thymidine 5′-phosphate in thymidine kinase deficient CCRF CEM cells. Biochem. Pharmacol.69 (9), 1307–1313 (2005).
   PubMed Web of Science ®Google Scholar
• Mackman RL , ZhangL, PrasadVet al. Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs. Bioorg. Med. Chem.15 (16), 5519–5528 (2007).
   PubMed Web of Science ®Google Scholar
• Gosselin G , GirardetJL, PerigaudCet al. New insights regarding the potential of the pronucleotide approach in antiviral chemotherapy. Acta. Biochim. Pol.43 (1), 195–208 (1996).
   Web of Science ®Google Scholar
• Perigaud C , GirardetJL, GosselinGet al. Comments on nucleotide delivery forms. Adv. Antivir. Drug Des.2, 147–172 (1996).
   Google Scholar
• Perigaud C , GosselinG, LefebvreIet al. Rational design for cytosolic delivery of nucleoside monophosphates: “SATE” and “DTE” as enzyme-labile transient phosphate protecting groups. Bioorg. Med. Chem. Lett.3 (12), 2521–2526 (1993).
   Web of Science ®Google Scholar
• Puech F , GosselinG, LefebvreIet al. Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process. Antivir. Res.22 (2–3), 155–174 (1993).
   PubMed Web of Science ®Google Scholar
• Peyrottes S , EgronD, LefebvreIet al. SATE pronucleotide approaches: an overview. Mini Rev. Med. Chem.4 (4), 395–408 (2004).
   PubMed Web of Science ®Google Scholar
• Morales EHR , BalzariniJ, MeierC. Diastereoselective synthesis of cycloSaligenyl-nucleosyl-phosphotriesters. Chem. A Eur. J.17 (5), 1649–1659 (2011).
   PubMed Web of Science ®Google Scholar
• Meier C , BalzariniJ. Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules. Antivir. Res.71 (2–3), 282–292 (2006).
   PubMed Web of Science ®Google Scholar
• Meier C , MeerbachA, BalzariniJ. Cyclosal-pronucleotides - Development of first and second generation chemical Trojan horses for antiviral chemotherapy. Front. Biosci.9 (1), 873–890 (2004).
   PubMedGoogle Scholar
• Meier C . CycloSal-pronucleotides-design of the concept, chemistry, and antiviral activity. Adv. Antivir. Drug Des.4, 147–213 (2004).
   Google Scholar
• Bookser BC , RaffaeleNB, ReddyKRet al. Synthesis of 3′-amino-3′-deoxyguanosine and 3′-amino-3′-deoxyxyloguanosine monophosphate hepdirect prodrugs from guanosine. Nucleosides Nucleotides Nucleic Acids28 (10), 969–986 (2009).
   PubMed Web of Science ®Google Scholar
• Erion MD , BulloughDA, LinCCet al. HepDirect prodrugs for targeting nucleotide-based antiviral drugs to the liver. Curr. Opin. Investig. Drugs.7 (2), 109–117 (2006).
   PubMedGoogle Scholar
• Vernachio JH , BleimanB, BryantKDet al. INX-08189, a phosphoramidate prodrug of 6-O-methyl-2′-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob. Agents. Chemother.55 (5), 1843–1851 (2011).
   PubMed Web of Science ®Google Scholar
• Mehellou Y , BalzariniJ, McGuiganC. Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells. Chem. Med. Chem.4 (11), 1779–1791 (2009).
   Google Scholar
• Cahard D , McGuiganC, BalzariniJ. Aryloxy phosphoramidate triesters as protides. Mini Rev. Med. Chem.4 (4), 371–381 (2004).
   PubMed Web of Science ®Google Scholar
• Cheng J , ZhouX, ChouTFet al. Identification of the amino acid-AZT-phosphoramidase by affinity T7 phage display selection. Bioorg. Med. Chem. Lett.19 (22), 6379–6381 (2009).
   PubMed Web of Science ®Google Scholar
• Chou TF , BaraniakJ, KaczmarekRet al. Phosphoramidate pronucleotides: A comparison of the phosphoramidase substrate specificity of human and Escherichia coli histidine triad nucleotide binding proteins. Mol. Pharm.4 (2), 208–217 (2007).
   PubMedGoogle Scholar
• Drontle DP , WagnerCR. Designing a pronucleotide stratagem: lessons from amino acid phosphoramidates of anticancer and antiviral pyrimidines. Mini Rev. Med. Chem.4 (4), 409–419 (2004).
   PubMed Web of Science ®Google Scholar
• Egron D , ImbachJL, GosselinGet al. S-Acyl-2-thioethyl phosphoramidate diester derivatives as mono-nucleotide prodrugs. J. Med. Chem.46 (21), 4564–4571 (2003).
   PubMed Web of Science ®Google Scholar
• Egron D , PerigaudC, GosselinGet al. Synthesis and study of a new series of phosphoramidate derivatives as mononucleotide prodrugs. Nucleosides Nucleotides Nucleic Acids20 (4–7), 751–754 (2001).
   PubMed Web of Science ®Google Scholar
• Beltran T , EgronD, PomponAet al. Rational design of a new series of pronucleotide. Bioorg. Med. Chem. Lett.11 (13), 1775–1777 (2001).
   PubMed Web of Science ®Google Scholar
• Satoh T . Role of carboxylesterases in xenobiotic metabolism. In : Reviews in Biochemical Toxicology. HodgsonE, BendJR, PhilpotRM ( Eds.). Elsevier, North Holland, 155–81 (1987).
   Google Scholar
• Jochum A , SchliengerN, EgronDet al. Biolabile constructs for pronucleotide design. J. Organomet. Chem.690 (10), 2614–2625 (2005).
   Web of Science ®Google Scholar
• Shafiee M , DefermeS, VillardA-Let al. New bis(SATE) prodrug of AZT 5′-monophosphate: in vitro anti-HIV activity, stability, and potential oral absorption. J. Pharm. Sci.90 (4), 448–463 (2001).
   PubMed Web of Science ®Google Scholar
• Atherton FR , OpenshawHT, ToddAR. Studies on phosphorylation. Part II. The reaction of dialkyl phosphites with polyhalogen compounds in presence of bases. A new method for the phosphorylation of amines. J. Chem. Soc.660–663 (1945).
   Web of Science ®Google Scholar
• Atherton FR , ToddAR. Studies on phosphorylation. Part III. Further observations on the reaction of phosphites with polyhalogen compounds in the presence of bases and its application to the phosphorylation of alcohols. J. Chem. Soc.674–678 (1947).
   PubMed Web of Science ®Google Scholar
• Perigaud C , PeyrottesS, DumontetC : WO2009053654 (2009).
   Google Scholar
• Mayes BA , ArumugasamyJ, BalogluEet al. Synthesis of a nucleoside phosphoramidate prodrug inhibitor of HCV NS5B polymerase: phenylboronate as a transient protecting group. Org. Process Res. Dev.18 (6), 717–724 (2014).
   Web of Science ®Google Scholar
• McGuigan C , PerroneP : WO2008062206 (2008).
   Google Scholar
• Maccoss M , OlsenDB : WO2006012078 (2006).
   Google Scholar
• McGuigan C , PathiranaRN, MahmoodNet al. Aryl phosphates derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT. Antivir. Res.17 (4), 311–321 (1992).
   PubMed Web of Science ®Google Scholar
• Iyer VV , GriesgraberGW, RadmerMRet al. Synthesis, in vitro anti-breast cancer activity, and intracellular decomposition of amino acid methyl ester and alkyl amide phosphoramidate monoesters of 3′-azido-3′-deoxythymidine (AZT). J. Med. Chem.43 (11), 2266–2274 (2000).
   PubMed Web of Science ®Google Scholar
• Valette G , PomponA, GirardetJLet al. Decomposition pathways and in vitro HIV inhibitory effects of isoddA pronucleotides: towards a rational approach for intracellular delivery of nucleoside 5′-monophosphates. J. Med. Chem.39 (10), 1981–1990 (1996).
   PubMed Web of Science ®Google Scholar
• Roman CA , WasserthalP, BalzariniJet al. Diastereoselective synthesis of (aryloxy)phosphoramidate prodrugs. Eur. J. Org. Chem. (25), 4899–4909 (2011).
   Web of Science ®Google Scholar
• Murakami E , TolstykhT, BaoHet al. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem.285 (45), 34337–34347 (2010).
   PubMed Web of Science ®Google Scholar
• Troev K , TashevE, BorisovG. On the interaction between dialkyl phosphites and amine hydrochlorides. Phosphorus Sulfur. Silicon. Relat. Elem.11 (3), 363–367 (1981).
   Web of Science ®Google Scholar
• Surleraux D , DoussonCB, GosselinGet al. US20130064794 (2013).
   Google Scholar
• Dhareshwar SS , StellaVJ. Your prodrug releases formaldehyde: should you be concerned? No!J. Pharm. Sci.97 (10), 4184–4193 (2008).
   PubMed Web of Science ®Google Scholar
• Jones RJ , BischofbergerN. Minireview: nucleotide prodrugs. Antivir. Res.27 (1–2), 1–17 (1995).
   PubMed Web of Science ®Google Scholar
• Cretton-Scott E , PerigaudC, PeyrottesSet al. In vitro antiviral activity and pharmacology of IDX184, a novel and potent inhibitor of HCV replication. J. Hepatol.48 (Suppl. 2), S220 (2008).
   Google Scholar
• Surleraux D , DoussonCB, ParsyCC : WO2013056046 (2013).
   Google Scholar
• Standring DN , LanfordR, Cretton-ScottEet al. Potent antiviral activity of second generation nucleoside inhibitors, IDX102 and IDX184, in HCV-infected chimpanzees. J. Hepatol.48 (Suppl. 2), S30 (2008).
   Google Scholar
• Standring DN , LanfordR, LiBet al. Antiviral activity of the liver-targeted nucleotide HCV polymerase inhibitor IDX184 correlates with trough serum levels of the nucleoside metabolite in HCV-infected chimpanzees. J. Hepatol.50 (Suppl. 1), S37 (2009).
   Google Scholar
• Standring DN , PerigaudC, PeyrottesSet al. Pharmacology of IDX184, a liver-targeted nucleotide prodrug for the treatment of HCV. Glob. Antivir. J.5 (Suppl. 1), 22 (2009).
   Google Scholar
• Lallos L , La CollaM, SerraIet al. Combination of IDX184, a nucleotide prodrug polymerase inhibitor, with other classes of HCV inhibitors is additive to synergistic in the HCV replicon in vitro. Hepatol.50 (Suppl. 4), 267A (2009).
   Web of Science ®Google Scholar
• La Colla M , LallosLB, SerraIet al. A triple combination of direct-acting antiviral agents demonstrates robust anti-HCV activity in vitro. J. Hepatol.52 (Suppl. 1), S299 (2010).
   Google Scholar
• Lam AM , EspirituC, BansalSet al. Hepatitis C virus nucleotide inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA. J. Virol.85 (23), 12334–12342 (2011).
   PubMed Web of Science ®Google Scholar
• Bilello JP , LallosLB, McCarvilleJFet al. In vitro activity and resistance profile of samatasvir, a novel NS5A replication inhibitor of hepatitis C virus. Antimicrob. Agents. Chemother.58 (8), 4431–4442 (2014).
   PubMed Web of Science ®Google Scholar
• Mayes BA , WangJ, ArumugasamyJet al. Scalable synthesis of a nucleoside phosphoramidate prodrug inhibitor of HCV NS5B RdRp: challenges in the production of a diastereomeric mixture. Org. Process Res. Dev.19 (4), 520–530 (2015).
   Web of Science ®Google Scholar
• Mayes BA , MoussaAM, Gasparac-KnezicRet al. Pharmaceutical compositions of 2′-C-methyl-guanosine,5′-[2[(3-hydroxy-2,2-dimethyl-1oxopropyl)thio]ethyl, N-(phenylmethyl)phosphoramidate]: US20130217644 (2013).
   Google Scholar
• Zhou XJ , PietropaoloK, ChenJet al. Safety and pharmacokinetics of IDX184, a liver-targeted nucleotide polymerase inhibitor of hepatitis C virus, in healthy subjects. Antimicrob. Agents. Chemother.55 (1), 76–81 (2011).
   PubMed Web of Science ®Google Scholar
• Zhou XJ , PietropaoloK, Sullivan-BolyaiJet al. IDX184, a liver-targeted nucleotide HCV polymerase inhibitor: results of a first-in-man safety and pharmacokinetic study. J. Hepatol.50 (Suppl. 1), S351 (2009).
   PubMedGoogle Scholar
• ClinicalTrials Database: NCT01157104. https://clinicaltrials.gov/ct2/show/NCT01157104.
   Google Scholar
• Idenix Press . Idenix Pharmaceuticals provides updates on three clinical development programs. Press release. http://ir.idenix.com/releasedetail.cfm?ReleaseID=611432.
   Google Scholar
• Lalezari J , AsmuthD, CasiroAet al. Short-term monotherapy with IDX184, a liver-targeted nucleotide polymerase inhibitor, in patients with chronic hepatitis C virus infection. Antimicrob. Agents. Chemother.56 (12), 6372–6378 (2012).
   PubMed Web of Science ®Google Scholar
• Lalezari J , PoordadF, MehraPet al. Antiviral activity, pharmacokinetics and safety of IDX184 in combination with pegylated interferon (PEGIFN) and ribavirin (RBV) in treatment-naive HCV genotype 1-infected subjects. J. Hepatol.52 (Suppl. 1), S469 (2010).
   PubMedGoogle Scholar
• Lalezari J , O'RiordanW, PoordadFet al. A Phase IIa study of IDX184 in combination with pegylated interferon (pegIFN) and ribavirin (RBV) in treatment-naive genotype 1 HCV-infected subjects. Hepatology52 (Suppl. 4), 337A (2010).
   Google Scholar
• Lalezari J , BoxT, O'RiordanWet al. IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C. Antivir. Ther.18 (6), 755–764 (2013).
   PubMed Web of Science ®Google Scholar
• McCarville JF , DubucG, DonovanEet al. No resistance to IDX184 was detected in 3-day and 14-day clinical studies of IDX184 in genotype 1-infected HCV subject. J. Hepatol.54 (Suppl. 1), S488–S489 (2011).
   Google Scholar
• Sheridan C . Calamitous HCV trial casts shadow over nucleoside drugs. Nat. Biotechnol.30 (11), 1015–1016 (2012).
   PubMed Web of Science ®Google Scholar
• Arnold JJ , SharmaSD, FengJYet al. Sensitivity of mitochondrial transcription and resistance of RNA polymerase II dependent nuclear transcription to antiviral ribonucleosides. PLoS Pathog.8 (11), e1003030 (2012).
   PubMed Web of Science ®Google Scholar
• FirstWord Pharma . Idenix Pharmaceuticals provides updates on IDX184 and IDX19368 development programs. Press release : www.firstwordpharma.com/node/1055565?tsid=17#axzz3WANE2q5f.
   Google Scholar
• Baudy RB , ButeraJA : WO2004092189 (2004).
   Google Scholar
• Ghose AK , CrippenG. Atomic physicochemical parameters for three dimensional structure-directed quantitative structure–activity relationships. I. Partition coefficient as a measure of hydrophobicity. J. Comput. Chem.7 (4), 567–577 (1986).
   Web of Science ®Google Scholar
• Viswanadhan VN , GhoseAK, RevankarGRet al. Atomic physicochemical parameters for three dimensional structure directed quantitative structure–activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J. Chem. Inf. Comp. Sci.29 (3), 163–172 (1989).
   Google Scholar
• Ghose AK , ViswanadhanVN, WendoloskiJJ. Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: an analysis of ALOGP and CLOGP methods. J. Phys. Chem. A.102 (21), 3762–3772 (1998).
   Web of Science ®Google Scholar
• Luo G , HamatakeRK, MathisDM, RacelaJ, RigatKL, ColonnoRJ. De novo initiation of RNA synthesis by the RNA-dependent RNA polymerase (NS5B) of hepatitis C virus. J. Virol.74, 851–863 (2000).
   PubMed Web of Science ®Google Scholar
• Zhu Q , GuoJT, SeegerC. Replication of hepatitis C virus subgenomes in nonhepatic epithelial and mouse hepatoma cells. J. Virol.77, 9204–9210 (2003).
   PubMed Web of Science ®Google Scholar