The summaries are free for public
use. The Chronic Liver Disease
Foundation will continue to add and
archive summaries of articles deemed
relevant to CLDF by the Board of
Trustees and its Advisors.
Abstract Details
Synergistic activity of combined NS5A inhibitors
O'Boyle DR 2nd1, Nower PT2, Gao M2, Fridell R2, Wang C2, Hewawasam P2, Lopez O2, Tu Y2, Meanwell NA2, Belema M2, Roberts SB2, Cockett M2, Sun JH2. Antimicrob Agents Chemother. 2015 Dec 28. pii: AAC.02639-15. [Epub ahead of print]
Author information
1Departments of Virology and Discovery Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA oboyled@bms.com.
2Departments of Virology and Discovery Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
Abstract
Daclatasvir (DCV) is a first in class hepatitis C virus (HCV) NS5A replication complex inhibitor (NS5A RCI) clinically effective in interferon-free combinations with direct acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potential in vitro, defining a new class of HCV inhibitors termed NS5A synergists : Sun et.al, Nature, 2015. doi: 10.1038/nature15711 : To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV+NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multi-log drop in HCV followed by rebound due to the emergence of resistance. DCV+NS5A-Syn combinations were highly efficient at clearing cells of viruses following the trend seen in replicon studies. Re-treatment of resistant viruses that emerged using DCV monotherapy with DCV+NS5A-Syn resulted in a multi-log drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on WT virus. A triple combination of DCV+NS5A-Syn and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV+NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy as well as tools to explore NS5A function.