Feb 25, 2019 · Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis. Many mutations of TTR have been identified; most of these are pathogenic, but some offer protective effects....

Apr 3, 2018 · TTR (transthyretin) cardiac amyloidosis is caused by dissociation of TTR into monomers, which misassemble into amyloid fibrils. TTR stabilizers act at the dimer–dimer interface to prevent dissociation.

Transthyretin (TTR) is a tetrameric transport protein highly conserved through vertebrate evolution and synthesized in the liver, choroid plexus, and retinal pigment epithelium. TTR transports the thyroid hormone thyroxine and the retinol-binding ...

Aug 22, 2022 · The dissociation of the transthyretin (TTR) tetramer into a monomer is closely related to various TTR amyloidoses in humans. While the tetramer dissociation has been reported to be the rate-limiting step for TTR aggregation, few details are known about the mechanism.

May 1, 2022 · Based on pathogenesis of the disease, new promising therapeutic strategies for ATTR amyloidosis have been developed. Effective disease-modifying therapies, such as TTR tetramer stabilizers and TTR gene silencing therapies, are now clinically available for patients with ATTRv amyloidosis in several countries or regions.

May 29, 2012 · Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K d s ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR.

Drawing from clinically investigated AG10, we designed a constrained congener (14) that exhibits excellent TTR tetramer binding potency, prevents TTR aggregation in a gel-based assay, and possesses desirable pharmacokinetics in mice.

Jul 8, 2021 · Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of proamyloidogenic 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 …

Feb 23, 2016 · Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are...

Nov 5, 2001 · TTR encodes transthyretin (TTR), a protein synthesized predominantly by the liver and secreted into plasma as a tetramer composed of four identical monomers. TTR is also synthesized in the retina and choroid plexus. TTR pathogenic variants reduce the stability of the TTR tetramer and produce a pro-amyloidogenic monomer. The amyloidogenic ...