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WORKING LUNCHEONE FUTURE THERAPIES

WORKING LUNCHEONE FUTURE THERAPIES. The Hep C Drug Pipeline. Nature 474, S6, 2010. chymotrypsin-like enzyme activation by NS4A cleaves viral and cellular proteins Polyprotein processing innate responses (TLR3, RIG-I). Structure of Membrane-Associated NS3/4A. helicase domain.

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WORKING LUNCHEONE FUTURE THERAPIES

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  1. WORKING LUNCHEONE FUTURE THERAPIES

  2. The Hep C Drug Pipeline Nature 474, S6, 2010

  3. chymotrypsin-like enzyme • activation by NS4A • cleaves viral and cellular proteins • Polyprotein processing • innate responses (TLR3, RIG-I) Structure of Membrane-Associated NS3/4A helicase domain protease domain NS4A protease cofactor Brass et al. PNAS 2008

  4. Boceprevir Telaprevir ‚macrocyclic‘ TMC435 MK5172 Structures of NS3-Specific Drugs ‚linear‘

  5. Translation Assembly Blockage of polyprotein cleavage block of new formation of replication vesicles no effect on established replication vesicels Restoration of innate immune response? RIG-I (MAVS) TLR3 (TRIF) Mode-of-Action of NS3-specific DAAs LD > 1.000 polyproteins 1 (+) RNA RV

  6. Resistance against PIs:2nd Generation EC50 > 4-fold Halfon & Locarnini, J. Hepatol. 2011

  7. The Hep C Drug Pipeline Nature 474, S6, 2010

  8. The NS5B RNA-Dependent RNA Polymerase Form of a right hand ‘closed’ active site Thumb Palm Fingers

  9. Nucleosidic Inhibitors 2'-C-methyl cytidine PSI-7977 INX-189 Non-nucleosidic Inhibitors Benzimidazole derivative Thiophene derivative Thiadiazine derivative Nucleosidic and Non-nucleosidic NS5B-Specific Drugs

  10. Translation Assembly Block of RNA synthesis direct effect also on established replication complexes direct inhibition of NS5B (non-nucs) block of elongation (nucs) Mode-of-Action of NS5B-Specific Inhibitors LD > 1.000 polyproteins 1 (+) RNA RV

  11. Higher Genetic Barrier of Nucsas compared to Non-Nucs and PIs NS5B Nuc NS5B Non-Nuc NS3/4A PI R7128 Active Moiety (PSI-6130) HCV-796 Telaprevir 1X IC50 10X IC50 15X IC50 1X IC50 10X IC50 15X IC50 Untreated 1X IC50 10X IC50 15X IC50 • R7128: 10x and 15x IC50 eliminated HCV replicons within ~3 weeks • no resistance detected • HCV-796: 10x and 15x IC50 did not eliminate the replicon • C316Y and S365S/A • Telaprevir: 10x and 15x IC50 did not eliminate the replicon • A156T/S and T54T/A

  12. The Hep C Drug Pipeline Nature 474, S6, 2010

  13. R R 2 classes of antivirals reported as „NS5A inhibitors“ R. DeFrancesco et al., 18th international Symposium on Hepatitis C virus and related viruses, Seattle, 2011 A-831:4-NH2-quinazolines (Arrow/AZ) BMS -790052 Resistance mutations in NS5A domain I: L31V, Y93H (gt 1b) M28T, Q30H/R, L31M/V, Y93C (gt 1a) Resistance mutations in NS5A domain I, II and III: L199F, T200P, E212D, P299L, I302T, V362A, S370P, V388D, S390G NS4B: S258T NS5B: S76A target NS5A PI4K-IIIα Schmitz & Tan, Rec Pat Antiinfect Drug Discov, 2008; Delang et al., Viruses 2010

  14. membrane D1 (polyU) D2 Basic groove D3 F. Penin F. Penin Structure of NS5A

  15. X X Mode-of-action of NS5A inhibitors NS5A inhibitors are dominant negative (1 inhibitor per 100 – 1.000 NS5A molecules) block of 5A oligomerization? block PI4K-IIIα activation? block NS5A hyperphosphorylation? Targett-Adams et al., JVi 2011

  16. Schmitz Recent Pat Antiinfect Drug Discov. 2008 Gao et al. Nature 465, 96-100 (2010) Resistance against NS5A inhibitorsin replicon studies

  17. The Hep C Drug Pipeline Nature 474, S6, 2010

  18. Cyclophilins • CyPs are chaperones with peptidyl-prolyl isomerase activity • Abundant cytosolic protein (0.1% of total cellular proteins) • Ubiquitously expressed in eukaryotic cells • Multiple functions, depending on target protein • Discovered as specific ligand for immunosuppressive drug cyclosporin A

  19. Inhibition of HCV replication by CsA Watashi et al., Hepatology 2003 Structure of CsA and CsA-Derivatives adapted from Gallay, Clin Liv Dis 2009

  20. Structure of Cyclophilin Inhibitors Alisporivir adapted from Gallay, Clin Liv Dis 2009 0.3nM ? Sanglifehrin 0.02µM

  21. CsA CsA CypA CypA CypA CypA CypA HCV replication HCV replication Mode-of-Action of Cyp Inhibitors? 3 3 5A 5A 5B 5B

  22. The Hep C Drug Pipeline Nature 474, S6, 2010

  23. IFN- IFNAR • IFN-α and IFN-λ share the same signalling pathways • Very similar set of ISGs induced • But: Receptor distribution very different • IFN-α receptor on most cells • IFN-λ receptor primarily on hepatocytes & airway epithelia • faster and prolonged ISG induction JAK / Stat dsRNA antiviral genes (~ 400) ISGF-3 ISRE ISG The Interferon System Virus vRNA dsRNA RIG-I TLR3 MAVS TRIF IFN- IFN- adapted from Haller et al., Virology, 2005

  24. SOC-based treatment of HCV infection:correlation with IL28B polymorphism High positive correlation with therapy outcome High correlation with outcome of acute therapy A special role of IFN-lambda to combat HCV? *Ge et al., Nature 2009; Suppiah et al., Nat Gen 2009; Tanaka et al., Nat Gen 2009 Thomas et al., Nature 2009;

  25. RIG-I MDA-5 IRF-1 IRF-2 IRF-7 MAP3K14 OASL RNaseL PKR RNA translation IFI44L GTPase NT5C3 nucleoside dephosph.? Viperin LDs? membrane curv? ADAR RNA editing DDIT4 ? signal transduction RNA degradation ISGs impairing HCV replication Multiple Attack Strategies Against HCV Schoggins et al., Nature 2011; Han et al., 2002; Gale et al., 1997; Helbig et al., 2005; Taylor et al., 2005

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