Core as a Novel Viral Target for Hepatitis C Drugs
Abstract
:1. Introduction
2. Core as a target protein for anti-HCV drug discovery
3. Core’s role in HCV’s life cycle
3.1. Core interactions with other HCV proteins
3.2. Core’s role in assembly
4. Core’s structure and function
5. Assays for analyzing core function:
a. Assays for Nucleocapsid formation
b. Core dimerization
- 1. For developing a sandwich ELISA, GST-tagged core106 domain was adsorbed on microplates coated with glutathione, and a horse-radish peroxidase goat anti-mouse antibody was used to demonstrate binding of anti-Flag antibody to Flag-tagged core106 itself bound to GST-core106 (Figure 3). This result demonstrated hetero-dimerization of the two fusion proteins. Free GST, Flag peptide or untagged core106 each displaced specific binding to background levels. [23].
- 2. The ELISA was useful to qualitatively demonstrate the interaction when using alternately tagged core106 fusion proteins, but the need for multiple washes hampered a precise analysis of the interaction, and precluded its use for screening of large compound libraries. For this purpose, a TR-FRET homogenous assay was developed, using the same GST-and Flag-tagged core106 proteins (Figure 4) [23,69]. Fluorophore-labeled antibodies against the GST and Flag tags allowed the authors to quantitatively measure the formation of dimers and oligomers of core106. The TR-FRET was particularly well adapted for robotized high-throughput screening in 384- and 1,536-well microplates of large small compound libraries [69]. The typical signal to background ratio shown in Figure 4 left, was rather low, although the inhibitory signal (Figure 4 right) was quite adequate for identifying “primary hit” inhibitors [69].
- 3. To develop a more sensitive assay for precise dose-response analyses, an AlphaScreen assay was developed, as a secondary format for monitoring core106 dimerization, but using donor and acceptor beads coated respectively with Glutathione or anti-Flag antibodies respectively, resulting in assays with at least 50-fold signal to background ratios (Figure 5) [23,70]. Again, untagged core106 domain was used as a reference inhibitor, with an IC50 of 89 nM [23]. While AlphaScreen beads are not easily handled by most robotic suites found in high-throughput screening laboratories, and sometimes vary in day-to-day stability, they provided a remarkably sensitive format for following chemical optimization of primary hit compounds first identified in large scale screening [70].
6. Inhibitors of core dimerization
6.1. Inhibition of core106 and core169 dimerization by peptides
6.2. Inhibitors of core dimerization by organic molecules
7. Inhibition of HCV production by inhibitors of core dimerization
7.1. Peptide inhibitors of HCV
7.2. Small compound inhibitors of HCV
7.3. Mode of action of inhibitors
7.3.1. Peptides
7.3.2. Small organic molecule inhibitors
8. Future developments
Acknowledgments
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Strosberg, A.D.; Kota, S.; Takahashi, V.; Snyder, J.K.; Mousseau, G. Core as a Novel Viral Target for Hepatitis C Drugs. Viruses 2010, 2, 1734-1751. https://doi.org/10.3390/v2081734
Strosberg AD, Kota S, Takahashi V, Snyder JK, Mousseau G. Core as a Novel Viral Target for Hepatitis C Drugs. Viruses. 2010; 2(8):1734-1751. https://doi.org/10.3390/v2081734
Chicago/Turabian StyleStrosberg, Arthur Donny, Smitha Kota, Virginia Takahashi, John K. Snyder, and Guillaume Mousseau. 2010. "Core as a Novel Viral Target for Hepatitis C Drugs" Viruses 2, no. 8: 1734-1751. https://doi.org/10.3390/v2081734
APA StyleStrosberg, A. D., Kota, S., Takahashi, V., Snyder, J. K., & Mousseau, G. (2010). Core as a Novel Viral Target for Hepatitis C Drugs. Viruses, 2(8), 1734-1751. https://doi.org/10.3390/v2081734