DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cells
2.2. Virus
2.3. Cell Viability Studies of Compounds
2.4. Evaluation of Anti-Viral Efficacy of Compounds
2.5. Plaque Assay
2.6. Viral RNA Extraction and Quantitative Real-Time RT-PCR (qRT-PCR)
2.7. Western Blot Analysis
2.8. Data Analysis
2.9. Statistical Analysis
2.10. Pseudovirus Entry Assay
2.11. Nsp13 Enzymatic Assay
2.12. SARS-CoV-2 nsp12 RNA Polymerase RNA Dependent (RdRp) Activity
3. Results
3.1. Inhibitors of DHFR Exert Anti-Viral Activity against SARS-CoV-2 in Two Cell Lines
3.2. PTX, TMX and MTX Inhibit the Activity of SARS-CoV-2 Viral Key Enzymes
3.3. DHFR Inhibitors also Inhibit SARS-CoV-2 Viral Entry
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Structures | Drug | IC50 (µM) | CC50 (µM) | SI |
---|---|---|---|---|
Pralatrexate | 0.004 | 0.008 | 2 | |
Trimetrexate | 0.007 | 0.01 | 1.4 | |
Methotrexate hydrate | 0.63 | 1.18 | 1.9 | |
Aminopterin | 1.3 | 2.49 | 1.9 | |
Pemetrexed disodium heptahydrate | 5 | 2.43 | 0.5 | |
Raltitrexed | 5 | 0.89 | 0.2 |
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Iaconis, D.; Caccuri, F.; Manelfi, C.; Talarico, C.; Bugatti, A.; Filippini, F.; Zani, A.; Novelli, R.; Kuzikov, M.; Ellinger, B.; et al. DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action. Viruses 2023, 15, 1128. https://doi.org/10.3390/v15051128
Iaconis D, Caccuri F, Manelfi C, Talarico C, Bugatti A, Filippini F, Zani A, Novelli R, Kuzikov M, Ellinger B, et al. DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action. Viruses. 2023; 15(5):1128. https://doi.org/10.3390/v15051128
Chicago/Turabian StyleIaconis, Daniela, Francesca Caccuri, Candida Manelfi, Carmine Talarico, Antonella Bugatti, Federica Filippini, Alberto Zani, Rubina Novelli, Maria Kuzikov, Bernhard Ellinger, and et al. 2023. "DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action" Viruses 15, no. 5: 1128. https://doi.org/10.3390/v15051128