Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Virus Propagation
2.3. Toxicity of Drug Combinations
2.4. Antiviral Testing
2.5. RNA Extraction and qRT-PCR
2.6. Determination of Infectious Titer
2.7. Statistical Analysis
3. Results
3.1. Antiviral Activity of Molnupiravir and Nirmatrelvir, Alone or in Combination
3.2. Antiviral Activity of GS-441524, Alone or in Combination with Molnupiravir and/or Nirmatrelvir
3.3. Antiviral Activity of Ivermectin, Alone or in Combination with Molnupiravir and/or Nirmatrelvir
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Concentration (µM) | Log10 Fold Change RNA | Infectious Titer | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Molnupiravir | PF-07321332 | GS-441524 | Ivermectin | 48 h | ±SD | 72 h | ±SD | IC | ±SD | Log10 TCID50/mL | ±SD |
30 | −3.69 | 0.33 | −3.94 | 0.07 | −4.62 | 0.04 | LOD | n/a | |||
10 | −4.13 | 1.23 | −3.20 | 0.43 | −3.43 | 0.34 | LOD | n/a | |||
5 | −2.02 | 0.38 | −0.85 | 0.16 | −0.83 | 0.26 | 2.50 | 0.71 | |||
2.5 | −0.74 | 0.06 | −0.47 | 0.02 | −0.28 | 0.14 | 4.17 | 0.24 | |||
1 | −0.21 | 0.10 | −0.21 | 0.19 | −0.23 | 0.20 | 5.88 | 0.96 | |||
0.5 | −0.17 | 0.01 | −0.07 | 0.07 | −0.08 | 0.04 | - | - | |||
0.1 | −0.32 | 0.06 | −0.03 | 0.01 | 0.06 | 0.05 | - | - | |||
5 | −4.79 | 0.13 | −4.17 | 0.64 | −4.96 | 0.03 | - | - | |||
1 | −4.14 | 0.83 | −3.99 | 0.16 | −4.80 | 0.38 | LOD | n/a | |||
0.5 | −3.80 | 0.23 | −4.10 | 0.18 | −4.82 | 0.31 | LOD | n/a | |||
0.2 | −3.20 | 0.10 | −2.97 | 0.67 | −3.39 | 0.74 | 3.36 | 1.41 | |||
0.1 | −2.28 | 0.86 | −0.93 | 0.60 | −0.73 | 0.56 | 5.83 | 0.81 | |||
0.05 | −0.44 | 0.21 | −0.19 | 0.12 | 0.00 | 0.16 | 6.31 | 0.46 | |||
0.01 | 0.22 | 0.06 | −0.13 | 0.26 | −0.05 | 0.15 | 6.00 | 0.00 | |||
10 | −3.89 | 0.12 | −3.85 | 0.74 | −4.79 | 0.21 | LOD | n/a | |||
5 | −3.07 | 0.22 | −4.07 | 0.27 | −5.31 | 0.17 | LOD | n/a | |||
3 | −3.33 | 0.34 | −3.38 | 0.33 | −4.40 | 0.38 | LOD | n/a | |||
1 | −1.12 | 0.11 | −0.88 | 0.10 | −1.67 | 0.15 | 5.72 | 0.84 | |||
0.3 | −0.01 | 0.08 | −0.16 | 0.12 | −0.26 | 0.19 | 6.48 | 0.73 | |||
10 | −0.83 | 0.08 | −0.55 | 0.17 | −0.69 | 0.19 | 3.89 | 0.97 | |||
5 | −0.70 | 0.09 | 0.27 | 0.05 | 0.30 | 0.07 | 6.25 | 0.25 | |||
2.5 | −0.78 | 1.07 | 0.06 | 0.24 | 0.45 | 0.14 | 6.17 | 0.24 | |||
1 | −0.31 | 0.24 | 0.17 | 0.14 | 0.29 | 0.19 | 6.33 | 0.47 | |||
0.5 | −0.08 | 0.08 | 0.02 | 0.12 | 0.26 | 0.19 | 6.33 | 0.47 | |||
0.25 | 0.16 | 0.20 | 0.04 | 0.08 | −0.13 | 0.17 | 6.58 | 0.73 | |||
0 | 0 | 0 | 0 | 0.16 | 0.20 | 0.01 | 0.06 | −0.01 | 0.06 | 6.45 | 0.32 |
Concentration (µM) | Log10 Fold Change RNA | Infectious Titer | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Molnupiravir | PF-07321332 | GS-441524 | Ivermectin | 48 h | ±SD | 72 h | ±SD | IC | ±SD | Log10 TCID50/mL | ±SD |
1 | −0.21 | 0.10 | −0.21 | 0.19 | −0.23 | 0.20 | 5.88 | 0.96 | |||
0.2 | −3.20 | 0.10 | −2.97 | 0.67 | −3.39 | 0.74 | 3.36 | 1.41 | |||
0.1 | −2.28 | 0.86 | −0.93 | 0.60 | −0.73 | 0.56 | 5.83 | 0.81 | |||
0.05 | −0.44 | 0.21 | −0.19 | 0.12 | 0.00 | 0.16 | 6.31 | 0.46 | |||
1 | −1.12 | 0.11 | −0.88 | 0.10 | −1.67 | 0.15 | 5.72 | 0.84 | |||
0.3 | −0.01 | 0.08 | −0.16 | 0.12 | −0.26 | 0.19 | 6.48 | 0.73 | |||
10 | −0.83 | 0.08 | −0.55 | 0.17 | −0.69 | 0.19 | 3.89 | 0.97 | |||
0.25 | 0.16 | 0.20 | 0.04 | 0.08 | −0.13 | 0.17 | 6.58 | 0.73 | |||
1 | 0.2 | −2.97 | 0.12 | −3.40 | 0.94 | −3.90 | 0.79 | 2.25 | 1.64 | ||
1 | 0.1 | −2.62 | 0.51 | −2.41 | 1.47 | −2.48 | 1.49 | 3.42 | 1.79 | ||
1 | 0.05 | −0.98 | 0.13 | −0.50 | 0.11 | −0.18 | 0.29 | 6.33 | 0.19 | ||
1 | 1 | −2.25 | 1.49 | −2.09 | 1.26 | −2.81 | 1.87 | 3.33 | 1.91 | ||
1 | 0.3 | −1.74 | 0.93 | −0.55 | 0.11 | −0.95 | 0.38 | 5.83 | 0.54 | ||
1 | 10 | −1.76 | 0.13 | −2.23 | 0.40 | −2.80 | 0.35 | 3.58 | 0.88 | ||
1 | 0.25 | −0.35 | 0.31 | −0.32 | 0.30 | −0.55 | 0.14 | 6.00 | 0.33 | ||
0.2 | 1 | −3.11 | 0.19 | −3.84 | 0.51 | −4.58 | 0.18 | 1.86 | 1.12 | ||
0.2 | 0.3 | −3.07 | 0.26 | −3.41 | 0.61 | −4.08 | 0.65 | 2.31 | 1.57 | ||
0.2 | 10 | −3.03 | 0.24 | −3.73 | 0.51 | −4.67 | 0.41 | 0.98 | 0.14 | ||
0.2 | 0.25 | −2.83 | 0.37 | −3.13 | 0.69 | −3.63 | 0.81 | 2.92 | 1.55 | ||
0.1 | 1 | −3.09 | 0.26 | −3.43 | 0.64 | −4.42 | 0.29 | 2.00 | 1.37 | ||
0.1 | 0.3 | −2.46 | 0.31 | −1.66 | 0.66 | −1.85 | 0.43 | 4.83 | 0.27 | ||
0.1 | 10 | −3.06 | 0.18 | −3.60 | 0.65 | −4.13 | 0.75 | LOD | n/a | ||
0.1 | 0.25 | −2.73 | 0.40 | −2.43 | 1.12 | −2.29 | 0.77 | 4.42 | 1.34 | ||
0.05 | 1 | −2.79 | 0.85 | −2.90 | 0.91 | −3.53 | 1.47 | 2.48 | 1.76 | ||
0.05 | 0.3 | −1.95 | 1.25 | −1.10 | 0.63 | −1.59 | 0.74 | 5.83 | 0.27 | ||
0.05 | 10 | −2.22 | 0.43 | −2.29 | 1.53 | −2.70 | 1.46 | 3.45 | 2.95 | ||
0.05 | 0.25 | −0.65 | 0.09 | −0.57 | 0.23 | −0.44 | 0.20 | 6.50 | 0.27 | ||
1 | 0.2 | 1 | −3.27 | 0.29 | −3.70 | 0.48 | −4.38 | 0.27 | 1.78 | 0.83 | |
1 | 0.1 | 1 | −3.29 | 0.24 | −3.53 | 0.38 | −4.30 | 0.12 | 1.89 | 1.08 | |
1 | 0.05 | 1 | −2.81 | 0.54 | −2.59 | 1.08 | −3.05 | 0.90 | 3.67 | 0.69 | |
1 | 0.2 | 0.3 | −2.95 | 0.15 | −3.37 | 0.52 | −3.89 | 0.12 | 1.70 | 1.24 | |
1 | 0.1 | 0.3 | −2.72 | 0.47 | −2.55 | 1.11 | −2.50 | 1.22 | 4.00 | 1.93 | |
1 | 0.05 | 0.3 | −1.27 | 0.36 | −0.73 | 0.65 | −1.20 | 0.68 | 5.50 | 0.86 | |
1 | 0.2 | 10 | −3.16 | 0.17 | −3.71 | 0.49 | −4.43 | 0.19 | LOD | n/a | |
1 | 0.1 | 10 | −3.14 | 0.25 | −3.26 | 0.40 | −3.64 | 0.51 | 1.51 | 1.11 | |
1 | 0.05 | 10 | −2.52 | 0.22 | −3.07 | 0.45 | −3.70 | 0.76 | 1.92 | 0.88 | |
1 | 0.2 | 0.25 | −2.89 | 0.33 | −3.20 | 0.52 | −3.55 | 0.43 | 3.08 | 0.69 | |
1 | 0.1 | 0.25 | −2.65 | 0.37 | −2.60 | 1.03 | −2.34 | 0.74 | 4.08 | 1.07 | |
1 | 0.05 | 0.25 | −1.15 | 0.22 | −0.80 | 0.40 | −0.87 | 0.19 | 5.42 | 0.57 | |
0 | 0 | 0 | 0 | 0.16 | 0.20 | 0.01 | 0.06 | −0.01 | 0.06 | 6.45 | 0.3 |
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Siegrist, D.; Jonsdottir, H.R.; Bouveret, M.; Boda, B.; Constant, S.; Engler, O.B. Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia. Pharmaceutics 2024, 16, 1262. https://doi.org/10.3390/pharmaceutics16101262
Siegrist D, Jonsdottir HR, Bouveret M, Boda B, Constant S, Engler OB. Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia. Pharmaceutics. 2024; 16(10):1262. https://doi.org/10.3390/pharmaceutics16101262
Chicago/Turabian StyleSiegrist, Denise, Hulda R. Jonsdottir, Mendy Bouveret, Bernadett Boda, Samuel Constant, and Olivier B. Engler. 2024. "Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia" Pharmaceutics 16, no. 10: 1262. https://doi.org/10.3390/pharmaceutics16101262
APA StyleSiegrist, D., Jonsdottir, H. R., Bouveret, M., Boda, B., Constant, S., & Engler, O. B. (2024). Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia. Pharmaceutics, 16(10), 1262. https://doi.org/10.3390/pharmaceutics16101262