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Novel HCV Inhibitors The UseNovel of Antivirals HCV toInhibitors Rapidly Contain Outbreaks of the Classical Swine Fever Virus Johan Neyts Rega Institute, KULeuven, Leuven Belgium Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Selective Inhibitors of HCV Replication that Target NS Proteins Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The NS2 cysteine protease NS2/3 cleavage is essential for replication and assembly N N C C Active Site 1 Active Site 2 Lorenz et al. Nature (2006) 442: 831-5 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The HCV NS3 serine protease N-terminal domain : a serine protease in the presence of the NS4A cofactor protein C-terminal domain : RNA helicase De Francesco et al. 2001 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS3 protease product based inhibitors carboxy-terminal hexapeptide products as an active-site affinity anchor BILN-2061 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Proof of concept with BILN-2061 (Ciluprevir) Lamarre et al., Nature. (2003) 426:186-9. Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Telaprevir monotherapy placebo 1250 mg q12h 450 mg q8h 750 mg q8h Reesink et al., Hepatology (2005) 42 : 234A Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The Major VX-950 and BILN2061 Resistance Mutations Do Not Cause Cross-resistance ITMN-191 Ciluprevir Lin, C. et al. J. Biol. Chem. (2004) 279:17508-17514 Telaprevir Boceprevir TMC435350 Others : GS9256 - BI201335 - BMS-650032 - RG7227 - IDX320 - ABT-450 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Resistance mutations selected by protease inhibitors T54T-V R155Q A156S/T D168V/A Telaprevir (VX950) XX Boceprevir X X TMC435350 XXX ITMN-191 X X Ciluprevir (BILN- XX X 2061) Adapted from Sheldon et al., (2007) Expert Opinion Anti-Infectives Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The NS3 Helicase as an Antiviral Target Dr. A. Brancale (Cardiff) Kim et al (1998) Structure. 15:89-100 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS4A/NS3 inhibitors Mutations located where extensive No cross resistance with (other) interactions with NS4A exist. NS3 and with NS5B inhibitors Yang et al., (2008), Antimicrob. Agents & Chemother. Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS4B as an Antiviral Target NS4B : difficult to express membrane protein that is believed to interact with viral RNA Binding assay of 3’ terminal –ssRNA (labelled) to <<< quantity of NS4B protein library screen Clemizole Einav et al., Nat. Biotech.2008 NS4B Further reading : Gouttenoire, Penin & Moradpour, Rev. Med. Virol (2010) Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A as an Antiviral Target BMS-790052 Membrane-associated phosphoprotein involved in replication and virus production. No enzymatic activity associated ER membrane Membrane Cytosol anchor AA 1 to 30 : membrane anchor,Resistance directing NS5Amutations to the likely ER located at Domain I (without α- Domain 1 the membrane interface helix) crystallizes as a AA 5 to 25 : amphipathic α-helix with a lipid colinear homodimer bilayer-associated hydrophobic face and a (Tellinghuize et al., solvent-exposed polar face Love et al.). Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A inhibitor (BMS-790052) BMS-790052 Not cross resistant with other HCV inhibitors 31, 30, 28, 23 93 Mutations in N-terminus of domain 1. If transitioning between dimer configurations is important for HCV replication BMS-790052 may possibly influence this transition. May possibly prevent formation of a multiprotein complex on ER membrane. Resistance mutations likely located atBlocks the the hyperphosphorylation of NS5A Gao et al., (2010) Nature membrane interface (essential role in the viral life cycle). Causes redistribution of NS5A Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A inhibitor (BMS-790052) Scheel et al., Hepatology, 2010 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A inhibitor (BMS-790052) Mean change in HCV RNA following a single oral dose Phase II studies (phase I study) combining BMS- 790052 with the NS3 protease inhibitor BMS-650032 are ongoing. This combination (alone or with PEGIFN and RBV) results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders Gao et al., (2010) Nature Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The NS5B RNA dependent RNA polymerase Bresanelli & Rey Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Nucleoside inhibitors MK-0608 R7128 : di-isobutyl ester prodrug of PSI-6130 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Benzimidazole/indoles Intramolecular contacts between the thumb and the finger domain may force the enzyme into an 1 ‘open’, inactive conformation O COOH H N HO N O N Cl Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Thiophene carboxylic acid / Pyranoindole / Dihydropyranone VCH-916, PF-868554/Filibuvir, 2 Met423 Leu419 N O S OH O Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Benzothiadiazine/Acylpyrrolidines ABT-333 ANA598, 3 O O O S O O N N N N O N Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Benzofuran CH O 3 N H O F S O O N OH C316F/Y C445F 4 3 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Combinations of Non Nuc NS5B Inhibitors Delay or Prevent Resistance Development Delang et al., 2011 J. Hepatol, in press Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Double and triple resistant variants Delang et al. , J. Hepatol, in press (2011) Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Discovery of the imidazopyridine GS-9190 (Tegobuvir) BPIP compound 1 compound 2 compound 3 F F F F N N N N N N N N N N N N Br Br Br CF3 HCV BVDV HCV BVDV HCV BVDV HCV BVDV EC50 >50 0.07 ± 0.02 EC50 3.0 ± 1.6 0.12 ± 0.01 EC50 0.6 ± 0.1 0.24 ± 0.12 EC50 0.2 ± 0.1 0.25 ± 0.09 CC50 80 ± 11 83 ± 20 CC50 136 ± 42 >33 CC50 >55 >100 CC50 >119 >100 compound 4 GS-327073 F F F F N N GS-9190 (Tegobuvir) N N N N HCV : 1nM / BVDV > 50µM O ~ 2000 cpds N CF3 Cl HCV BVDV HCV BVDV 9 EC50 0.1 ± 0.01 0.72 ± 0.19 EC50 0.004 ± 0.002 1.4 ± 0.96 CC50 108 >100 CC50 ≥ 19 >100 ~ 1700 Vliegen et al. (2009), J. Hepatol. molecules Purstinger et al., (2006 b, c) Bioorg. Med. Chem. Letters Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus GS-9190 (Tegobuvir) targets the HCV RdRp with a GS-9190 (Tegobuvir)unique mechanism targets the HCV RdRp C445F - Y448H - Y452H - C316F/Y Beta hairpin loop involved in primer independent initiation of RNA replication. Partially cross resistant with benzofurans Compound does not inhibit the purified RdRp. Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Tegobuvir Phase IIa study (196-0112) Zeuzem et al., 61st AASLD (The Liver Meeting, Nov. 2010) Boston. Treatment-naive adults with chronic HCV genotype 1 (28-days treatment course) GS-9190 (40 mg twice daily) Median maximal decline from baseline GS-9256 (75 mg twice daily) HCV RNA of 4.1 log10 IU/mL GS-9190 (40 mg twice daily) Median maximal decline from baseline in GS-9256 (75 mg twice daily) HCV RNA of 5.1 log10 IU/mL. RBV (500 - 600 mg twice daily) GS-9190 (40 mg twice daily) 14/14 patients : HCV RNA < 25 IU/mL) at day 28. Median maximal decline from GS-9256 (75 mg twice daily) baseline in HCV RNA 5.7 log10 IU/mL RBV (500 - 600 mg twice daily) 13/14 patients : undetectable viral levels Peg-IFN (180 µg, inj. once/week) (HCV RNA < 10 IU/mL) at day 28. No virologic breakthroughs Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Tegobuvir + Telaprevir 3 day antiviral combination assay Clearance rebound assay No compound 5 x EC50 G418 pressure 100 80 120 60 100 40 80 20 60 0 40 -20 expected -40 20 -60 0.00015 0 0.0014 -80 Percentage of UTC (%) 0.012 C0 C1 C2 C3 R1 R2 R3 R4 % inhibition above or below -100 GS-9190 0.11 (µM) 1.0 1.0 0.33 0.11 VX-950 0.037 0.012 0.0041 VX-950 (µM) 0.0014 GS-073 + VX-950 0.00046 GS-073 Vliegen et al., J. Hepatol. 2009 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Triple combinations Clearence/rebound GS9190-9xEC50 Clearence/rebound GS9190-25xEC50 Clearence/rebound GS9190-125xEC50 R4 R4 R4 100 R3 ►►100 R3 100 R3 rebound rebound C3R1 DEATH rebound % replicon % replicon 75 R2 passage 75 R2 passage % replicon 75 R2 passage RNA as RNA as RNA as 50 number 50 number 50 number compared to R1 compared to R1 compared to R1 control 25 control 25 control 25 R0 R0 R0 0 0 0 123456 123456 123456 clearence passage number clearence passage number clearence passage number Clearence/rebound 2'CMC-9xEC50 Clearence/rebound
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