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MECHANISM OF HCV REPLICON RESISTANCE TO PSI-352938, A CYCLIC MONOPHOSPHATE PRODRUG OF 2'-alfa-F-2'-beta-C-METHYLGUANOSINE
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Reported by Jules Levin
EASL 2011 Berlin March 31-Apr 2
A.M. Lam, C. Espiritu, S. Bansal, H.M. Micolochick Steuer, V. Zennou, M.J. Otto, P.A. Furman
Pharmasset Inc., Princeton, NJ, USA.
EASL: PROTON Study: PSI-7977 QD with PEG/RBV: 12-week Safety, RVR, cEVR, & SVR12 in Treatment-naïve Patients with HCV GT2 or GT3 - (04/01/11)
EASL: ONCE DAILY DUAL-NUCLEOTIDE COMBINATION OF PSI-938 AND PSI-7977 PROVIDES 94% HCV RNA < LOD AT DAY 14: FIRST PURINE/PYRIMIDINE CLINICAL COMBINATION DATA (THE NUCLEAR STUDY) - (03/31/11)
EASL: PSI-7977 QD Plus PEG/RBV In HCV GT1: 98% Rapid Virologic Response, Complete Early Virologic Response: The PROTON Study - (03/31/11)
Eurpopean Association for the Study of the Liver
March 30th - April 3rd 2011 Berlin, Germany
Author Conclusions
· Selection studies were performed using PSI-352938 in GT 1a, 1b, and 2a replicon cells. We were unable to select for replicon-based resistance in GT 1a and 1b replicon cells, but GT 2a replicon developed resistance to PSI-352938.
· The PSI-352938 selected 2a replicon was not cross resistant to PSI-6130, PSI-7977, IDX-184, and INX-189.
· Sequence analysis identified a number of mutations within JFH-1 HCV NS5B, including S15G, R222Q, C223Y/H, L320I, and V321I. Residues R222, C223, L320, and V321 are within the Palm domain with close proximity to the conserved D220 and D318 residues, while S15 is located on the finger domain. L320 and V321 are just adjacent to the highly conserved GDD motif.
· Combinations of at least three amino acid changes (S15G/C223H/V321I) are required for a significant loss of sensitivity to PSI-352938 (>10-fold).
· The C223Y/H mutation was lethal for the GT 1b replicon. GT 1b replicon containing the triple mutation A15G/C223H/V321I was resistant to PSI-352938, but replicated at only 10% efficiency of the WT.
Introduction
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