Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cells and Viruses
2.2. Antiviral Activity of Natural Products
2.3. Detection of In Vitro Cytotoxicity
2.4. Time-of-Addition Experiment
2.5. ELISA
2.6. Surface Plasmon Resonance (SPR)
2.7. Combinatorial Effects of Gossypol with Other Natural Products against ZIKV Infection
3. Results
3.1. Identification of Lead Natural Products with Broad-Spectrum Activity against Multiple ZIKV Strains
3.2. Inhibition Mechanisms of Lead Natural Products against ZIKV Infection
3.3. Identification of Potential Binding Regions of Lead Natural Products in ZIKV Proteins
3.4. Combinatorial Effects of the Combinations of Gossypol with Other Natural Products against ZIKV Infection and Their Cytotoxicity to Vero E6 Cells
3.5. Potent Inhibitory Activity of Lead Natural Products, Particularly Gossypol, against Infections of DENV-1–4 Strains
4. Discussion
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Parameters | No. (%) |
---|---|
Natural products from MicroSource Discovery Systems for screening | 720 |
Primary hits (with inhibition against ZIKV strain PAN2016) a | 61 (8.5) |
Primary hits (with high cytotoxicity in Vero E6 cells) b | 38 (5.3) |
Specific hits (primary hits with low cytotoxicity) | 23 (3.2) |
Specific hits (available to purchase) | 16 (2.2) |
Specific hits (ordered from Sigma and retested to confirm anti-ZIKV activity) | 6 (0.8) |
Specific hits displaying IC50 < CC50 | 4 (0.6) |
Natural | IC50 (μM) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Products | CC50 (μM) | PAN2016 | R116265 | PAN2015 | FLR | R103451 | PRVABC59 | PLCal_ZV | IbH 30656 | MEX 2–81 | MR 766 |
Gossypol | 14.17 ± 0.74 | 3.48 ± 0.03 | 4.20 ± 0.08 | 3.95 ± 0.05 | 0.21 ± 0.01 | 2.28 ± 0.10 | 4.31 ± 0.02 | 1.98 ± 0.07 | 3.31 ± 0.11 | 2.79 ± 0.01 | 3.75 ± 0.01 |
Curcumin | 52.86 ± 0.52 | 13.67 ± 0.72 | 14.04 ± 0.15 | 13.71 ± 0.37 | 16.57 ± 0.34 | 11.22 ± 0.37 | 12.85 ± 0.35 | 10.84 ± 0.73 | 13.63 ± 0.31 | 5.62 ± 0.52 | 11.42 ± 0.29 |
Digitonin | 56.29 ± 1.20 | 4.31 ± 0.23 | 6.52 ± 0.59 | 5.00 ± 0.01 | 3.34 ± 0.22 | 4.30 ± 0.43 | 3.76 ± 1.12 | 3.19 ± 0.25 | 5.5.30 ± 0.13 | 3.84 ± 0.12 | 3.77 ± 0.31 |
Conessine | 323.71 ± 0.25 | 9.75 ± 0.26 | 7.18 ± 0.13 | 7.98 ± 0.29 | 9.65 ± 0.58 | 11.60 ± 0.33 | 9.08 ± 0.33 | 8.11 ± 0.37 | 10.25 ± 0.41 | 10.94 ± 0.06 | 7.44 ± 0.11 |
Bortezomib | 16.96 ± 0.20 | 9.75 ± 0.03 | 8.94 ± 0.10 | 9.88 ± 0.12 | 9.62 ± 0.59 | 14.14 ± 0.85 | 11.72 ± 0.82 | 31.04 ± 0.71 | 9.35 ± 0.23 | 7.67 ± 0.31 | 9.51 ± 0.26 |
Natural Product | IC50 (μM) | Fold of Enhancement | Natural Products | IC50 (μM) | Fold of Enhancement | CI | ||
---|---|---|---|---|---|---|---|---|
Alone | In Mixture | Alone | In Mixture | |||||
Gossypol | 3.79 ± 0.01 | 0.93 ± 0.04 | 3.08 | Curcumin | 13.20 ± 0.81 | 3.67 ± 0.18 | 2.60 | 0.52 |
3.79 ± 0.01 | 1.08 ± 0.19 | 2.51 | Digitonin | 4.85 ± 0.24 | 1.51 ± 0.27 | 2.21 | 0.60 | |
3.79 ± 0.01 | 0.81 ± 0.11 | 3.68 | Conessine | 10.04 ± 0.25 | 2.26 ± 0.30 | 3.44 | 0.44 | |
3.79 ± 0.01 | 1.00 ± 0.02 | 2.79 | Bortezomib | 10.65 ± 0.01 | 2.79 ± 0.06 | 2.82 | 0.53 |
Natural Product | IC50 (μM) | Fold of Enhancement | Natural Products | IC50 (μM) | Fold of Enhancement | CI | ||
---|---|---|---|---|---|---|---|---|
Alone | In Mixture | Alone | In Mixture | |||||
Gossypol | 0.26 ± 0.01 | 0.06 ± 0.01 | 3.33 | Curcumin | 17.05 ± 0.08 | 4.44 ± 0.74 | 2.84 | 0.49 |
0.26 ± 0.01 | 0.12 ± 0.01 | 1.17 | Digitonin | 3.86 ± 0.02 | 1.89 ± 0.13 | 12.04 | 0.95 | |
0.26 ± 0.01 | 0.10 ± 0.01 | 2.60 | Conessine | 10.07 ± 0.45 | 4.73 ± 0.08 | 1.13 | 0.85 | |
0.26 ± 0.01 | 0.05 ± 0.01 | 4.20 | Bortezomib | 9.70 ± 0.76 | 2.40 ± 0.28 | 3.04 | 0.44 |
Natural Product | IC50 (μM) | Fold of Enhancement | Natural Products | IC50 (μM) | Fold of Enhancement | CI | ||
---|---|---|---|---|---|---|---|---|
Alone | In Mixture | Alone | In Mixture | |||||
Gossypol | 4.38 ± 0.08 | 0.65 ± 0.06 | 5.74 | Curcumin | 12.46 ± 0.05 | 1.93 ± 0.16 | 5.46 | 0.30 |
4.38 ± 0.08 | 0.63 ± 0.10 | 5.95 | Digitonin | 3.84 ± 0.81 | 0.55 ± 0.09 | 5.98 | 0.29 | |
4.38 ± 0.08 | 0.62 ± 0.01 | 6.06 | Conessine | 9.40 ± 0.21 | 1.29 ± 0.01 | 6.29 | 0.28 | |
4.38 ± 0.08 | 0.45 ± 0.02 | 8.73 | Bortezomib | 12.17 ± 0.07 | 1.07 ± 0.04 | 10.37 | 0.19 |
Natural Product | CC50 (μM) | Fold of Enhancement | Natural Products | CC50 (μM) | Fold of Enhancement | CI | ||
---|---|---|---|---|---|---|---|---|
Alone | In Mixture | Alone | In Mixture | |||||
Gossypol | 14.84 ± 0.42 | 13.70 ± 0.05 | 0.08 | Curcumin | 53.12 ± 1.83 | 41.36± 1.93 | 0.28 | 1.70 |
14.84 ± 0.42 | 16.01 ± 0.40 | ‒0.07 | Digitonin | 50.63 ± 0.22 | 14.05 ± 0.35 | 2.60 | 1.36 | |
14.84 ± 0.42 | 15.16 ± 0.80 | ‒0.02 | Conessine | 314.57 ± 2.32 | 46.39 ± 2.94 | 5.78 | 1.17 | |
14.84 ± 0.42 | 6.31 ± 0.62 | 1.35 | Bortezomib | 17.77 ± 0.17 | 17.53 ± 1.73 | 0.01 | 1.41 |
Natural Products | IC50 (μM) | ||||
---|---|---|---|---|---|
CC50 (μM) | DENV-1-V1792 | DENV-2-V594 | DENV-3-V1043 | DENV-4-PR 06-65-740 | |
Gossypol | 14.54 ± 0.59 | 1.87 ± 0.01 | 1.89 ± 0.21 | 3.70 ± 0.59 | 2.60 ± 0.12 |
Curcumin | 59.42 ± 1.18 | 9.37 ± 0.47 | 3.07 ± 0.07 | 2.09 ± 0.12 | 4.83 ± 0.24 |
Digitonin | 59.02 ± 0.33 | 5.21 ± 0.35 | 6.56 ± 0.21 | 4.07 ± 0.83 | 6.44 ± 0.34 |
Conessine | 302.69 ± 13.40 | 7.09 ± 0.08 | 6.61 ± 0.60 | 7.41 ± 0.04 | 7.27 ± 0.31 |
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Gao, Y.; Tai, W.; Wang, N.; Li, X.; Jiang, S.; Debnath, A.K.; Du, L.; Chen, S. Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors. Viruses 2019, 11, 1019. https://doi.org/10.3390/v11111019
Gao Y, Tai W, Wang N, Li X, Jiang S, Debnath AK, Du L, Chen S. Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors. Viruses. 2019; 11(11):1019. https://doi.org/10.3390/v11111019
Chicago/Turabian StyleGao, Yaning, Wanbo Tai, Ning Wang, Xiang Li, Shibo Jiang, Asim K. Debnath, Lanying Du, and Shizhong Chen. 2019. "Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors" Viruses 11, no. 11: 1019. https://doi.org/10.3390/v11111019
APA StyleGao, Y., Tai, W., Wang, N., Li, X., Jiang, S., Debnath, A. K., Du, L., & Chen, S. (2019). Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors. Viruses, 11(11), 1019. https://doi.org/10.3390/v11111019