| Autor: |
Seguin SP; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Evans CW, Nebane-Akah M, McKellip S, Ananthan S, Tower NA, Sosa M, Rasmussen L, White EL, Maki BE, Matharu DS, Golden JE, Aubé J, Brodsky JL, Noah JW |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of biomolecular screening [J Biomol Screen] 2012 Feb; Vol. 17 (2), pp. 194-203. Date of Electronic Publication: 2011 Sep 23. |
| DOI: |
10.1177/1087057111421630 |
| Abstrakt: |
The authors conducted a high-throughput screening campaign for inhibitors of SV40 large T antigen ATPase activity to identify candidate antivirals that target the replication of polyomaviruses. The primary assay was adapted to 1536-well microplates and used to screen the National Institutes of Health Molecular Libraries Probe Centers Network library of 306 015 compounds. The primary screen had an Z value of ~0.68, signal/background = 3, and a high (5%) DMSO tolerance. Two counterscreens and two secondary assays were used to prioritize hits by EC(50), cytotoxicity, target specificity, and off-target effects. Hits that inhibited ATPase activity by >44% in the primary screen were tested in dose-response efficacy and eukaryotic cytotoxicity assays. After evaluation of hit cytotoxicity, drug likeness, promiscuity, and target specificity, three compounds were chosen for chemical optimization. Chemical optimization identified a class of bisphenols as the most effective biochemical inhibitors. Bisphenol A inhibited SV40 large T antigen ATPase activity with an IC(50) of 41 µM in the primary assay and 6.2 µM in a cytoprotection assay. This compound class is suitable as probes for biochemical investigation of large T antigen ATPase activity, but because of their cytotoxicity, further optimization is necessary for their use in studying polyomavirus replication in vivo. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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