Format

Send to

Choose Destination
J Med Chem. 2017 Sep 28;60(18):7820-7834. doi: 10.1021/acs.jmedchem.7b00952. Epub 2017 Sep 18.

Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation.

Author information

1
Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
2
Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
3
Department of Bacteriology, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.

Abstract

Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR·ligand complexes. The ensuing structure-function data led to a symmetrical diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-molecule drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.

PMID:
28920684
PMCID:
PMC5659721
DOI:
10.1021/acs.jmedchem.7b00952
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center