Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40–CD154 Costimulatory Protein-Protein Interaction
Abstract
:1. Introduction
2. Results
2.1. Design and Synthesis
2.2. Binding Inhibition Assays
2.3. Binding Partner (Protein Thermal Shift)
2.4. In Vitro Activity
Inhibition of CD154-Induced NF-κB Activation in Sensor Cells
2.5. In Vivo Activity
Inhibition of Alloantigen-Induced Immune Response
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Chemistry
4.3. Binding Assays
4.4. Protein Thermal Shift (Differential Scanning Fluorimetry)
4.5. CD40 Sensor Cell Assay
4.6. Cytotoxicity Assay
4.7. Animal Care and Treatment
4.8. Draining Lymph Node
4.9. Statistics and Data Fitting
5. Conclusions
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
CI | confidence interval |
PPI | protein-protein interaction |
T1D | type 1 diabetes |
TNF | tumor necrosis factor |
TNFSF | TNF superfamily |
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Sample Availability: Not available. |
No. | Name | Formula | R1 a | R2 a | CD40 IC50 [μM] | OX40 IC50 [μM] | BAFF IC50 [μM] | TNF IC50 [μM] | NF-κB IC50 [μM] |
---|---|---|---|---|---|---|---|---|---|
6 | DRI-C21041 | C30H21N3O7S | 1-SO3H | 4′-NO2 | 0.087 | 317.9 | 0.328 | >1000 | 19.9 |
7 | DRI-C24041 | C30H21N3O7S | 4-SO3H | 4′-NO2 | 0.299 | 9.34 | 2.007 | 554.6 | |
8 | DRI-21047a | C31H21F3N2O5S | 1-SO3H | 4′-CF3 | 57.85 | 10.07 | 42.18 | 61.07 | |
9 | DRI-C24541 | C32H23N3O6 | 4-CO2Me | 4′-NO2 | 55.99 | >1000 | 685.6 | 795.8 | |
10 | DRI-C2105041 | C30H21N3O10S2 | 1,5-(SO3H)2 | 4′-NO2 | 68.31 | 135.0 | 439.7 | 688.5 | |
11 | DRI-C2105045 | C32H24N2O10S2 | 1,5-(SO3H)2 | 4′-CO2Me | 60.07 | 120.4 | 540.1 | 456.1 | |
12 | DRI-C2104121 | C30H20N4O9S | 1-SO3H | 2′,4′-(NO2)2 | 50.50 | 10.31 | 38.14 | 61.68 | |
13 | DRI-C2104531 | C32H23N3O9S | 1-SO3H | 3′-NO2-4′-CO2Me | 0.390 | 86.19 | 5.27 | 674.4 | |
14 | DRI-C21091 | C36H25N3O7S | 1-SO3H | 4′-(4-NO2)C6H4 | 0.020 | 6.88 | 0.784 | 70.35 | 11.1 |
15 | DRI-C21095 | C38H28N2O7S | 1-SO3H | 4′-(4-CO2Me)C6H4 | 0.019 | 1.013 | 1.517 | 26.55 | 6.0 |
16 | DRI-C31041 | C32H25N3O7S | 1-SO3H | 4′-NO2 | 44.80 | 7.28 | 26.73 | 61.48 | |
17 | DRI-C41041 | C28H19N3O7S | 1-SO3H | 4′-NO2 | 57.45 | 36.63 | 81.38 | 118.5 | |
18 | DRI-C61041 | C29H20N4O7S | 1-SO3H | 4′-NO2 | 1.34 | 5.48 | 8.07 | 46.94 | 8.7 |
19 | DRI-C61045 | C31H23N3O7S | 1-SO3H | 4′-CO2Me | 2.41 | 6.97 | 13.76 | 182.0 |
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Bojadzic, D.; Chen, J.; Alcazar, O.; Buchwald, P. Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40–CD154 Costimulatory Protein-Protein Interaction. Molecules 2018, 23, 1153. https://doi.org/10.3390/molecules23051153
Bojadzic D, Chen J, Alcazar O, Buchwald P. Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40–CD154 Costimulatory Protein-Protein Interaction. Molecules. 2018; 23(5):1153. https://doi.org/10.3390/molecules23051153
Chicago/Turabian StyleBojadzic, Damir, Jinshui Chen, Oscar Alcazar, and Peter Buchwald. 2018. "Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40–CD154 Costimulatory Protein-Protein Interaction" Molecules 23, no. 5: 1153. https://doi.org/10.3390/molecules23051153
APA StyleBojadzic, D., Chen, J., Alcazar, O., & Buchwald, P. (2018). Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40–CD154 Costimulatory Protein-Protein Interaction. Molecules, 23(5), 1153. https://doi.org/10.3390/molecules23051153