Using Molecular Tweezers to Remodel Abnormal Protein Self-Assembly and Inhibit the Toxicity of Amyloidogenic Proteins

Ravinder Malik; Jing Di; Gayatri Nair; Aida Attar; Karen Taylor; Edmond Teng; Frank-Gerrit Klärner; Thomas Schrader; Gal Bitan

doi:10.1007/978-1-4939-7811-3_24

Using Molecular Tweezers to Remodel Abnormal Protein Self-Assembly and Inhibit the Toxicity of Amyloidogenic Proteins

Methods Mol Biol. 2018:1777:369-386. doi: 10.1007/978-1-4939-7811-3_24.

Authors

Ravinder Malik¹, Jing Di¹, Gayatri Nair¹, Aida Attar^{1

2}, Karen Taylor¹, Edmond Teng^{1

3}, Frank-Gerrit Klärner⁴, Thomas Schrader⁴, Gal Bitan^{5

6

7}

Affiliations

¹ Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
² Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, USA.
³ Greater Los Angeles Healthcare System, Veterans Hospital, West Los Angeles, CA, USA.
⁴ Faculty of Chemistry, University of Duisburg-Essen, Essen, Germany.
⁵ Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu.
⁶ Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu.
⁷ Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu.

Abstract

Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein self-assembly, which act by binding selectively to lysine and arginine residues. Through this unique mechanism of action, MTs inhibit formation of toxic oligomers and aggregates. Their efficacy and safety have been demonstrated in vitro, in cell culture, and in animal models. Here, we discuss the application of MTs in diverse in vitro and in vivo systems, the experimental details, the scope of their use, and the limitations of the approach. We also consider methods for administration of MTs in animal models to measure efficacy, pharmacokinetic, and pharmacodynamic parameters in proteinopathies.

Keywords: Alzheimer’s disease; Amyloid; Amyloidosis; Blood–brain barrier; Parkinson’s disease; Protein aggregation; Proteinopathy; Synaptic toxicity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyloidogenic Proteins / chemistry*
Animals
Blood-Brain Barrier / metabolism
Cell Line
Cells, Cultured
Humans
Mice
Models, Molecular*
Molecular Structure
Protein Aggregates
Protein Aggregation, Pathological
Protein Multimerization*
Proteins / chemistry*

Substances

Amyloidogenic Proteins
Protein Aggregates
Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding