Chiral metallohelical complexes enantioselectively target amyloid β for treating Alzheimer's disease.

Abstract

Stereochemistry is a very important issue for the pharmaceutical industry and can determine drug efficacy. The design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid-β (Aβ) aggregation, represent valid therapeutic strategies for treatment of Alzheimer's disease (AD). Herein we report that two triple-helical dinuclear metallosupramolecular complexes can act as a novel class of chiral amyloid-β inhibitors. Through targeting α/β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit Aβ aggregation, which is demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, this is the first report of enantioselective inhibition of Aβ aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood-brain barrier and have superoxide dismutase activity. It is well-known that chiral discrimination is important for understanding chiral drug action. Generally, one enantiomer is pharmaceutically active while the other is inactive or exerts severe side effects. Chiral discrimination should be important for AD treatment. Our work provides new insights into chiral inhibition of Aβ aggregation and opens a new avenue for design and screening of chiral agents as Aβ inhibitors against AD.

• Authors: Meng Li, Suzanne E Howson, Kai Dong, Nan Gao, Jinsong Ren, Peter Scott, Xiaogang Qu
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 136 Issue 33 Pg. 11655-63 (Aug 20 2014) ISSN: 1520-5126 [Electronic] United States
• PMID: 25062433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Organometallic Compounds
• Reactive Oxygen Species
• Superoxide Dismutase

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (antagonists & inhibitors, metabolism)
• Animals
• Models, Molecular
• Organometallic Compounds (chemistry, pharmacology)
• PC12 Cells
• Rats
• Reactive Oxygen Species (metabolism)
• Stereoisomerism
• Superoxide Dismutase (metabolism)
• Tumor Cells, Cultured