Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications
Abstract
:1. Introduction
2. Materials and Methods
2.1. Compounds
2.2. Cells
2.3. Preparation of EBOV trVLPs and Entry Reporter VLPs
2.4. trVLP Infection and Parallel Cell Viability Assays
2.5. VLP Entry and Parallel Cell Viability Assays
2.6. Analysis of Eight-Point Dose Response Data
3. Results
3.1. The Two Clomiphene Isomers and Their Primary Metabolites Block EBOV Entry and Replication
3.2. Clomiphene, Enclomiphene, and Zuclomiphene Inhibit EBOV trVLP Infection and VLP Entry with Equal Potency
3.3. Enclomiphene Blocks trVLP Infection in Vero E6 Cells as well as Entry Mediated by the Makona EBOV and Angola MARV GPs
4. Discussion
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Drug | Assay | Set 1 | Set 2 | ||
---|---|---|---|---|---|
IC50 (μM) | IC90 (μM) | IC50 (μM) | IC90 (μM) | ||
Clomiphene | trVLP | 1.2 | 1.4 | 0.9 | 2.2 |
Entry | 1.4 | 4.1 | 2.9 | 4.4 * | |
Enclomiphene | trVLP | 1.0 | 2.8 | ||
Entry | 1.2 | 1.6 | |||
Zuclomiphene | trVLP | 1.2 | 1.4 | ||
Entry | 2.2 | 5.6 |
Compound Administered | Compound Analyzed | Dose (mg) a | Route | Sex | Status | Ave. of n | C (max) (μM) | AUC (ng/mL/h) (last time) | T (max) | T 1/2 (h) | Ref. |
---|---|---|---|---|---|---|---|---|---|---|---|
Clomiphene | 50 | Oral | F | Healthy | 24 | [37] | |||||
Enclomiphene b | 0.02 | 42 (24 h) | 3.7 | --- | |||||||
Zuclomiphene b | 0.02 | 662 (288 h) | 6.8 | --- | |||||||
Clomiphene | 50 | Oral | F | Anov. | 9 | [45] | |||||
Enclomiphene | 0.01 | 65 (72 h) | 3 | --- | |||||||
Zuclomiphene | 0.04 | 1289 (456 h) | 7 | --- | |||||||
Clomiphene | 50 | IV | F | Anov. | [49] | ||||||
Enclomiphene | N/A, P1 | 0.66 | 373 (24 h) | --- | 60 | ||||||
N/A, P2 | 1.21 | 862 (24 h) | --- | 283 | |||||||
Zuclomiphene | N/A, P1 | 0.15 | 134 (24 h) | --- | 341 | ||||||
N/A, P2 | 0.26 | 255 (24 h) | 802 | ||||||||
Enclomiphene | Enclomiphene c | 25 | oral | M | ITT | 16 | 0.04 | --- | 2.5 | --- | [41] |
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Nelson, E.A.; Barnes, A.B.; Wiehle, R.D.; Fontenot, G.K.; Hoenen, T.; White, J.M. Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications. Viruses 2016, 8, 206. https://doi.org/10.3390/v8080206
Nelson EA, Barnes AB, Wiehle RD, Fontenot GK, Hoenen T, White JM. Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications. Viruses. 2016; 8(8):206. https://doi.org/10.3390/v8080206
Chicago/Turabian StyleNelson, Elizabeth A., Alyson B. Barnes, Ronald D. Wiehle, Gregory K. Fontenot, Thomas Hoenen, and Judith M. White. 2016. "Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications" Viruses 8, no. 8: 206. https://doi.org/10.3390/v8080206