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ChemRxiv_ACPHS-14.pdf (2.15 MB)

Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction

submitted on 24.02.2021, 15:33 and posted on 25.02.2021, 12:14 by Christopher L. Cioffi, Arun Raja, Parthasarathy Muthuraman, Aravindan Jayaraman, Srinivasan Jayakumar, Andras Varadi, Boglarka Racz, Konstantin Petrukhin

Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of pro-amyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener (18a) that exhibits excellent TTR tetramer binding potency, prevents TTR aggregation in a gel-based assay, and possesses desirable pharmacokinetics in mice. Additionally, 18a significantly lowers murine serum retinol-binding protein 4 (RBP4) levels despite a lack of binding at that protein’s all-trans-retinol site. We hypothesize that kinetic stabilization of TTR tetramers via 18a is allosterically hindering all-trans-retinol-dependent RBP4-TTR tertiary complex formation and that the compound could present ancillary therapeutic utility for indications treated with RBP4 antagonists, such as macular degeneration.


NIH Grant R01EY028549

NIH Grant P30 EY019007


Email Address of Submitting Author


Columbia University



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no competing financial interest.