Design and Development of Structure-Based Small Molecule Inhibitors of Amyloid Protein Assembly and Neurotoxicity.
We are developing novel compounds that inhibit the formation of that toxic protein aggregates that cause Alzheimer's disease, including those of amyloid β-protein and tau. We use a rational, structure-based approach in the design of the compounds, based on the latest knowledge of the molecular interactions and forces that control the formation of the aggregation process. Unlike traditional attempts to develop inhibitors of protein self-assembly, which have focused on disruption of a protein structure called β-pleated sheet, our compounds interfere with particular sets of molecular interactions that happen during the initial self-assembly steps of these proteins, before formation of β-pleated sheets.
|Sponsors:||Jim Easton Consortium for Alzheimer's Disease Drug Development and Biomarker Discovery at UCLA, American Health Assistance Foundation, UCLA Center for Gene-Environment Studies in Parkinson's Disease, Michael J. Fox Foundation, Team Parkinson/Parkinson Alliance and RJG Foundation.|
|Principal Investigator:||Gal Bitan, PhD|
|Collaborators:||Thomas Schrader, PhD and Frank Klärner, PhD from University of Duisburg-Essen, Germany, and Sally Frautschy, PhD, Jeff Bronstein, MD, PhD, and Marie-Françoise Chesselet, MD, PhD from University of California, Los Angeles, USA.|
Publications (selected peer-reviewed)
- S Sinha, DHJ Lopes, Z Du, ES Pang, A Shanmugam, A Lomakin, P Talbiersky, A Tennstaedt, K McDaniel, R Bakshi, P-Y Kuo, M Ehrmann, GB Benedek, JA Loo, F-G Klärner, T Schrader, C Wang, and G Bitan. Lysine-specific molecular tweezers are broad-spectrum inhibitor of aggregation and toxicity of amyloid proteins. J. Am. Chem. Soc. 2011; 133(42): 16958–16969.
- S Sinha, Z Du, P Maiti, F-G Klärner, T Schrader, C Wang, and G Bitan. Comparison of Three Amyloid Assembly Inhibitors: The Sugar scyllo-Inositol, the Polyphenol Epigallocatechin Gallate, and the Molecular Tweezer CLR01. ACS Chem. Neurosci. 2012; 3(6): 451-458.
- S Sinha, DHJ Lopes, and G Bitan. A Key Role for Lysine Residues in Amyloid β-Protein Folding, Assembly, and Toxicity. ACS Chem. Neurosci. 2012; 3(6): 473-481.
- T Liu and G Bitan. Modulating Self-Assembly of Amyloidogenic Proteins as a Therapeutic Approach for Neurodegenerative Diseases: Strategies and Mechanisms. ChemMedChem. 2012; 7: 359-374.
- A Attar, C Ripoli, E Riccardi, P Maiti, DD Li Puma, T Liu, J Hayes, MR Jones, K Lichti-Kaiser, F Yang, GD Gale, C-h Tseng, M Tan, C-W Xie, JL Straudinger, F-G Klärner, T Schrader, SA Frautschy, C Grassi and G Bitan. Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers. Brain. 2012; 135(Pt 12): 3735-3748.
- A Attar, F Rahimi, and G Bitan. Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01. Translational Neuroscience. 2013; 4(4): 385-409.
- A Attar, W-TC Chan, F-G Klärner, T Schrader, and G Bitan. Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins’ toxicity. BMC Pharm. Tox. 2014; 15(23): doi:10.1186/2050-6511-15-23.
- A Attar and G Bitan. Disrupting self-assembly and toxicity of amyloidogenic protein oligomers by ” molecular tweezers” – from the test tube to animal models, Curr. Pharm. Des. 2014; 20: 2469-2483.
- X Zheng, D-Y Liu, F-G Klärner, T Schrader, G Bitan, and MT Bowers. Amyloid β-protein Assembly: The Effect of Molecular Tweezer CLR01 and CLR03. J. Phys. Chem. B, 2015; 119: 4831-4841.
- R Malishev, S Nandi, S Kolusheva, Y Levi-Kalisman, F-G Klärner, T Schrader, G Bitan*, and R Jelinek*, Toxicity inhibitors protect lipid membranes from disruption by Aβ42, ACS Chem. Neurosci. 2015; 6: 1860-1869.
- T Schrader, G Bitan, and F-G Klärner, Molecular Tweezers for Lysine and Arginine – Powerful Inhibitors of Pathologic Protein Aggregation, Chem. Commun. 2016; 52: 11318-11334.
- R Malik, J Di, G Nair, A Attar, K Taylor, E Teng, F-G Klärner, T Schrader, and G Bitan, Using molecular tweezers to remodel abnormal protein self-assembly and inhibit the toxicity of amyloidogenic proteins.Methods Mol. Biol. 2018, 1777: 369-386.
- M Nshanian, C Lantz, P Wongkongkathep, T Schrader, F-G Klärner, A Blümke, C Despres, M Ehrmann, C Smet-Nocca, G Bitan, and JA Loo, Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator J. Am. Soc. Mass Spectrom. 2018,DOI: 10.1007/s13361-018-2027-6.
- C Despres, J Di, F-X Cantrelle, Z Li, I Huvent, B Chambraud, J Zhao, J Chen, S Chen, G Lippens, F Zhang, R Linhardt, C Wang, F-G Klärner, T Schrader, I Landrieu, G Bitan, and Caroline Smet-Nocca (2019) Major differences between the self-assembly and seeding behavior of heparin-induced- and in-vitro-phosphorylated tau and their modulation by potential inhibitors. ACS Chem. Biol., 14: 1363-1379.
- I Hadrovic, P Rebmann, F-G Klärner, G Bitan, and T Schrader (2019) Molecular Lysine Tweezers Counteract Aberrant Protein Aggregation. Front. Chem. 7: 657.
- AJ Mason, I Hurst, R Malik, I Siddique, I Solomonov, I Sagi, F-G Klärner, T Schrader, and G Bitan (2020) Different Inhibitors of Aβ42-Induced Toxicity Have Distinct Metal-Ion Dependency. ACS Chem. Neurosci. 11: 2243–2255.
- J Di, I Siddique, Z Li, G Malki, S Hornung, S Dutta, I Hurst, E Ishaaya, A Wang, S Tu, A Boghos, I Ericsson, F-G Klärner, T Schrader, and G Bitan (2021) The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice. Alz. Res. Ther., 13: 6.
- 2011-2012 Cure Alzheimer’s Fund “Molecular tweezers – novel inhibitors of amyloidogenic proteins and promising drug candidates for Alzheimer’s disease”
- 2012 NIH/NCRR UL1 TR000124 – UCLA Clinical and Translational Science Institute (CTSI) Voucher “A mouse toxicity study of a novel drug candidate”
- 2015-2016 Cure Alzheimer’s Fund 20152631 “Optimization of pharmacologic properties of molecular tweezers”
- 2015-2017 CurePSP Foundation 600-6-15 “Small-molecule modulation of tau clearance and aggregation”
- 2015-2020 NIH/NIA R01AG050721 “Misfolded protein clearance enhancers for Alzheimer’s therapy”