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HCV Genome and Protein Processing

HCV Genome and Protein Processing. Presentation Prepared by: David Spach, MD Last Updated: July 18, 2011. Hepatitis C Genome and Protein Processing. Hepatitis C Genome. HCV Genome. 5´ Non-coding Region. 3´ Non-coding Region. Positive-sense, single strand RNA, ≈ 9,600 base pairs.

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HCV Genome and Protein Processing

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  1. HCV Genome and Protein Processing Presentation Prepared by: David Spach, MD Last Updated: July 18, 2011

  2. Hepatitis C Genome and Protein Processing

  3. Hepatitis C Genome HCV Genome 5´ Non-coding Region 3´ Non-coding Region Positive-sense, single strand RNA, ≈ 9,600 base pairs

  4. Hepatitis C GenomeRegions Coding for Structural & Non-Structural Proteins HCV Genome 5´ Non-coding Region 3´ Non-coding Region Genes Coding for Structural Proteins Genes Coding for Non-Structural (NS) Proteins

  5. Hepatitis C GenomeStructural and Nonstructural Genes HCV Genome 5´ Non-coding Region 3´ Non-coding Region Genes Coding for Structural Proteins Genes Coding for Non-Structural (NS) Proteins C E1 E2 p7 NS2 NS3 A B A B NS4 NS5

  6. Hepatitis C GenomeInternal Ribosomal Entry Site (IRES) HCV Genome 5´ Non-coding Region 3´ Non-coding Region IRES C E1 E2 p7 NS2 NS3 A B A B NS4 NS5 Internal Ribosomal Entry Site (IRES) - Consists of Domains II, III, IV of the 5´ NCR and first 24-40 nucleotides of core region- IRES involved in processing of polypeptide precursor

  7. Hepatitis C VirusTranslation HCV Genome 5’ NCR 3’ NCR Translation Polyprotein Precursor C E1 E2 p7 NS2 NS3 A B A B NS4 NS5

  8. Hepatitis C VirusTranslation HCV Genome 5’ Non-coding Region 3’ Non-coding Region Translation C E1 E2 p7 NS2 NS3 A B A B NS4 NS5 Polyprotein Precursor: ≈ 3,000 amino acids

  9. Hepatitis C VirusProtein Processing HCV Genome Translation Polyprotein Precursor C E1 E2 p7 NS2 NS3 A B A B NS4 NS5 Protein Processing Signal Peptidase NS2/3 Protease NS3/4A Protease C E1 E2 p7 NS2 NS3 A B A B NS4 NS5

  10. Hepatitis C VirusProtein Processing HCV Genome Translation Polyprotein Precursor C E1 E2 p7 NS2 NS3 A B A NS4 B NS5 Protein Processing Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

  11. Hepatitis C VirusStructural and Nonstructural Proteins Hepatitis C Proteins Structural Proteins Nonstructural (NS) Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Nucleocapsid Envelope Glycoprotein CysteineProtease Serine Protease Cofactors RNA binding and assembly recognition complex Envelope Glycoprotein Vioporin Serine Protease RNAHelicase Membranous Web Induction RNA-Dependent RNA Polymerase

  12. Hepatitis C VirusTranslation Enzymes Involved in Protein Processing Polyprotein Precursor Signal Peptidase NS2/3 Protease NS3/4A Serine Protease C E1 E2 p7 NS2 NS3 A B A NS4 B NS5

  13. Hepatitis C GenomeTranslation Protein ProcessingRole of NS3/4A Serine Protease Polyprotein Precursor Signal Peptidase NS2/3 Protease NS3/4A Serine Protease C E1 E2 p7 NS2 NS3 A B A NS4 B NS5 Protein Processing Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

  14. Hepatitis C VirusNS3/4A Serine Protease Inhibitors NS3/4A Serine Protease Inhibitors Polyprotein Precursor Signal Peptidase NS2/3 Protease NS3/4A Serine Protease C E1 E2 p7 NS2 NS3 A B A NS4 B NS5 Proteins A B A NS4 C E1 E2 p7 NS2 NS3 B NS5

  15. Hepatitis C NS3/4a Serine Protease

  16. Hepatitis C VirusNS3 Protein NS3 Nonstructural (NS) proteinSize = 632 amino acids

  17. Hepatitis C VirusNS3 Protein Helicase Serine Protease Nonstructural (NS) proteinSize = 632 amino acids Components: Helicase (C-terminal) & Serine Protease (N-terminal)

  18. Hepatitis C Virus NS3 Protein 1 3 Helicase 2 Serine Protease Serine Protease Helicase Domain 1 Helicase Domain 2 HelicaseDomain 3 N-Terminal Region C-Terminal Region 1-187 188-326 327-480 481-632 Amino Acid

  19. Hepatitis C Virus NS3/4A Protein Complex NS3 NS4A NS3 Complexed with NS4A

  20. Hepatitis C VirusNS3/4A Serine Protease Active Site Helicase NS3 Protease Active Site Protease NS4A

  21. Hepatitis C Virus NS3/4A Serine Protease Inhibitor Helicase NS3 Protease Inhibitor Protease Active Site Protease NS4A

  22. Hepatitis C Virus NS3/4A Protein Complex NS3 NS4A NS3 Complexed with NS4A

  23. Hepatitis C Virus NS3/4A Serine Protease Inhibitors • Products FDA-Approved- Telaprevir (Incivek): three times daily dosing- Boceprevir (Victrelis): three times daily dosing • Products in Phase 3 Development- BI201335: once daily dosing • Products in Phase 2 Development- Danoprevir (R7227): twice daily dosing - Vaniprevir (MK-7009): twice daily dosing - TMC435350: once daily dosing- MK-5172: once daily dosing- ACH-1625: once daily dosing- GS-9256: twice daily dosing

  24. Questions?

  25. HCV Targets for Direct-Acting Antivirals (DAAs) Source: Pereira AA, et. al. Nat Rev Gastroenterol Hepatol. 2009;6:403-11.

  26. HCV Targets for Direct-Acting Antivirals (DAAs) Source:

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