1 / 26

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.

jaclyn
Download Presentation

HCV Genome and Protein Processing

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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:

More Related