 |
|
|
| |
Preclinical Characterization of GSK2485852A, a Novel HCV Polymerase Inhibitor
|
| |
| |
Reported by Jules Levin
EASL 2011, March 30 - April 3, 2011, Berlin, Germany
"GSK2485852A reduced HCV RNA levels 4 logs or 5 logs in genotype 1a and 1b replicons, respectively. ......GSK2485852A is an inhibitor of the HCV NS5B polymerase and is highly active with EC50 values in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell-culture system"
C. Voitenleitner1, R. Crosby1, A. Wang1, J. Bechtel1 , Mi Xie1, J. Pouliot1, E. Woldu1, S. Van Horn2, J. Horton1, K. Creech1, L.H. Carballo1, S. You1,
K. Remlinger1, J. Vamathevan3, J. B. Shotwell1, A. Spaltenstein1, Z. Hong1 and R. Hamatake1
1GlaxoSmithKline, Research Triangle Park, NC, USA; 2GlaxoSmithKline, Upper Providence, PA, USA, 3GlaxoSmithKline, Stevenage, UK
Abstract
The search for direct acting antiviral (DAA) compounds that act against targets on the Hepatitis C virus or host proteins that play a crucial role in the replication of this virus is of high importance since the current standard of care does not achieve a sustained virological response (SVR) in many patients even after an extended treatment period.
GSK2485852A is an inhibitor of the HCV NS5B polymerase and is highly active with EC50 values in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell-culture system. In an attempt to elucidate potency of GSK2485852A beyond the standard replicon assays, we used chimeric replicon systems with NS5B genes from different genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotype 1a and 1b. The inhibitory activity of GSK2485852A remained unchanged on these intergenotypic and intragenotypic replicon systems. GSK2485852A furthermore displays an excellent resistance profile and shows less than a five-fold potency loss across clinically important NS5B resistance mutations like S282T, P495L, M423T, C316Y or Y448H. A diverse mutant panel tested also revealed a lack of cross resistance against known resistance mutations against other viral proteins. Data from both 454 and population sequencing showed a pattern of mutations arising in the NS5B RNA dependent RNA polymerase. GSK2485852A shows superior viral RNA reductions of up to five logs in genotype 1b replicons.
Fluorescence quenching binding assays with GSK2485852A and purified NS5B protein showed that GSK2485852A had a slow off rate with a long predicted dissociation half life from the purified enzyme of approximately 8 hours.
Taken together these data suggest that GSK2485852A is a potent inhibitor of HCV replicons of various genotypes. Virological properties like a 'flat' resistance profile across multiple targets and biochemical characteristics like the long half life of dissociation from NS5B suggest that GSK2485852A may show a very favorable low dose efficacy in the clinic.
|
| |
|
|
|
|
|
