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WORKING LUNCHEONE FUTURE THERAPIES

This article discusses the current state of the Hepatitis C drug pipeline and the potential future therapies for treating the disease. It covers various drug targets, modes of action, and resistance mechanisms in the development of antiviral drugs. Additionally, it explores the role of cyclophilins, interferons, and innate immune responses in combating Hepatitis C.

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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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