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Safe Inhibition of Amyloid Proteins Toxicity without Protein Specificity
Author(s) -
Bitan Gal
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.564.2
Subject(s) - amyloid (mycology) , chemistry , amyloid disease , protein aggregation , biophysics , protein folding , biochemistry , microbiology and biotechnology , in vitro , biology , amyloid fibril , disease , medicine , amyloid β , inorganic chemistry , pathology
The distinctive 3D structures of proteins have been optimized by a hundred million years of evolution allowing them to recognize their substrates with very high specificity. Thus, drugs targeting enzymes/receptors must compete specifically and bind with high affinity, typically, in the nanomolar range. In contrast, abnormal self‐assembly of amyloid proteins into toxic oligomers and fibrils was not optimized and may, in fact, be a process evolution selected against. Therefore, the forces mediating the abnormal assembly process are substantially weaker. This is why the resulting oligomers are metastable and the nucleation of amyloid fibrils is a rare event. Consequently, we hypothesized that safe remodeling of the abnormal assembly process to inhibit formation of toxic species could be achieved using compounds that bind with moderate affinity and low specificity. We reasoned that binding of such compounds to stable proteins would not affect their structure or function. We tested this hypothesis using “molecular tweezers” that bind selectively to exposed Lys residues. Supporting our hypothesis, a lead tweezer named CLR01 was found to remodel the assembly and inhibit the toxicity of multiple amyloid proteins in vitro and in vivo without affecting normal physiology. CLR01 showed beneficial therapeutic effects in animal models of Alzheimer's disease, Parkinson's disease, and familial amyloid polyneuropathy and was found to have a high safety margin. The data show that misfolded‐protein clearance enhancers, such as CLR01, act by a unique mechanism that is specific to a process rather than to a particular protein, representing a novel approach to designing drugs for the currently cureless amyloid‐related diseases. The presentation will discuss the mechanism and present unpublished data demonstrating the unique action and therapeutic potential of our approach.