In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 121, No. suppl_1 ( 2017-07-21)
Abstract:
Nucleoside-derived structures constitute important Direct-Acting Antivirals (DAAs) for Hepatitis C Virus (HCV) treatment. BMS-986094 (BMS-094: a 2’-C-modified guanosine (G) derivative prodrug) was discontinued in phase II due to heart/kidney failure and cardiomyopathy, whereas sofosbuvir (a 2’-C-modified uridine prodrug) is an effective HCV DAA. Given the importance of purine nucleosides in cardiac signaling, we investigated BMS-094 in the human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) model (iCells, CDI Fujifilm). Beating myocyte monolayer impedance signals were monituored for up to 7 days in the RTCA Cardio platform (ACEA-Biosystems). BMS-094 was acutely myotoxic at high concentrations (≥ 17 μM), as evidenced by cessation of myocyte beating and loss of baseline impedance or ‘Cell Index’ (C.I.), a measure of cell adherence, within hours. On prolonged exposure to BMS-094 at concentrations not associated with loss of C.I. ( 〈 1 μM), we observed progressive, dose-dependent decreases in impedance amplitude (myocyte contractility) which were accompanied by increases in the spontaneous myocyte beating rate. The same beating phenotype could be elicited over a multi-day exposure duration by extracellular application of the BMS-094 core nucleoside (2’-C-methyl-guanosine) alone, but not by unmodified G. Loss of contractility with the G derivatives was accompanied by a decrease of the Ca 2+ transient amplitude in a Ca 2+ influx fluorescence assay (FDSS μCell, Hamamatsu). We investigated the impact of purine or pyrimidine base substitutions in the 2’-CMe-modified nucleoside: 2’-CMe-adenosine, -cytidine, -G, and -uridine. The uridine analog had the most limited effects on hiPSC-CMs beating parameters. The effect of 2’-CMe-cytidine on beating rate and impedance amplitude was similar to that of the G derivative, including a progressive multi-day onset. In contrast, 2’-CMe-adenosine slowed beating acutely, and led to loss of C.I. at higher concentrations. These results demonstrate the varied effects on CM function of base substitutions in antiviral nucleoside chemistry and support the utility of hiPSC-CMs as a model for screening in-vitro the potential cardiotoxicities of nucleoside derivative drugs.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.121.suppl_1.288
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
1467838-X
Permalink
