Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease
Abstract
:1. Introduction
2. Results
2.1. BL6 Synthesis
2.2. Molecular Docking
2.3. ADMET Properties
2.4. Effects of BL6 on the Cell Viability of SIM-A9 Cells Treated with a High Dose of LPS
2.5. Effects of BL6 on NO Production and Inflammatory Cytokines Induced by LPS in SIM-A9 Cells
2.6. BL6 May Promote M1 to M2 Microglial Polarization in SIM-A9 Cells Stimulated by LPS
2.7. Involvement of the PI3K/Akt/NF-κB Pathway in the Anti-Inflammatory Effects of BL6
2.8. BL6 Had No Protective Effect on STZ-Induced Neuro-2a Cytotoxicity
2.9. BL6 Reduced Icv-STZ-Induced Glial Activation in the Mouse Hippocampus
2.10. Effect of BL6 on GFAP, Synaptophysin, and p-Tau Levels in the Hippocampus of Icv-STZ-Treated Mice
3. Discussion
4. Materials and Methods
4.1. Synthesis of BL6
4.2. Cell Culture
4.3. Preparation of the Icv-STZ Mouse Model and BL6 Administration
4.4. Cell Viability Detection
4.5. Nitric Oxide (NO) Detection
4.6. Inflammatory Cytokine Detection
4.7. Immunoblot
4.8. Immunofluorescence Staining
4.9. Statistical Analysis
4.10. Molecular Docking and ADMET Profiling
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Property | Characteristics | Value |
---|---|---|
Physicochemical Properties | Molecular Weight | 409.28 |
TPSA | 47.56 | |
logS (Aqueous Solubility) | −4.973 log mol/L (Poor) | |
logP | 5.713 log mol/L | |
logD | 4.263 log mol/L | |
Medicinal Chemistry | Lipinski Rule | Accepted |
Absorption | Caco-2 Permeability ** | −4.809 cm/s (Excellent) |
HIA * | 0.008 (Excellent) | |
F20% * | 0.006 (Excellent) | |
F30% * | 0.043 (Excellent) | |
Distribution | PPB (%) | 98.37 (Poor) |
VD (L/kg) | 2.888 (Excellent) | |
BBB penetration * | 0.018 cm/s (Excellent) | |
Metabolism (CYP450 Inhibition) | CYP1A2 Inhibitor * | 0.251 (Active) |
CYP2C19 Inhibitor * | 0.764 (Active) | |
CYP2C9 Inhibitor * | 0.771 (Active) | |
CYP2D6 Inhibitor * | 0.25 (Active) | |
CYP3A4 Inhibitor * | 0.137 (Active) | |
Excretion | CL (mL/min/kg) | 3.382 |
t1/2 (hr) *** | 0.152 | |
Toxicity | hERG Blockers * | 0.019 µM (Excellent) |
H-HT * | 0.79 (Toxic) | |
AMES Toxicity * | 0.543 (Moderately toxic) | |
Respiratory Toxicity * | 0.019 (Non-Toxic) |
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Zhang, X.; Subbanna, S.; Williams, C.R.O.; Canals-Baker, S.; Hashim, A.; Wilson, D.A.; Weiss, L.M.; Shukla, S.; Chokkalingam, P.; Das, S.; et al. Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease. Molecules 2025, 30, 620. https://doi.org/10.3390/molecules30030620
Zhang X, Subbanna S, Williams CRO, Canals-Baker S, Hashim A, Wilson DA, Weiss LM, Shukla S, Chokkalingam P, Das S, et al. Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease. Molecules. 2025; 30(3):620. https://doi.org/10.3390/molecules30030620
Chicago/Turabian StyleZhang, Xiuli, Shivakumar Subbanna, Colin R. O. Williams, Stefanie Canals-Baker, Audrey Hashim, Donald A. Wilson, Louis M. Weiss, Srushti Shukla, Parthiban Chokkalingam, Sasmita Das, and et al. 2025. "Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease" Molecules 30, no. 3: 620. https://doi.org/10.3390/molecules30030620
APA StyleZhang, X., Subbanna, S., Williams, C. R. O., Canals-Baker, S., Hashim, A., Wilson, D. A., Weiss, L. M., Shukla, S., Chokkalingam, P., Das, S., Das, B. C., & Saito, M. (2025). Methionine Aminopeptidase 2 (MetAP2) Inhibitor BL6 Attenuates Inflammation in Cultured Microglia and in a Mouse Model of Alzheimer’s Disease. Molecules, 30(3), 620. https://doi.org/10.3390/molecules30030620