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Updated: Jun 17, 2026
Selection of Aptamers for Amyloid β-Protein, the Causative Agent of Alzheimer's Disease
Published on: May 13, 2010
A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent
Sungwook Choi1, Natàlia Reixach, Stephen Connelly
1Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA.
Abstract:
Transthyretin aggregation-associated proteotoxicity appears to cause several human amyloid diseases. Rate-limiting tetramer dissociation and monomer misfolding of transthyretin (TTR) occur before its aggregation into cross-beta-sheet amyloid fibrils. Small molecule binding to and preferential stabilization of the tetrameric state of TTR over the dissociative transition state raises the kinetic barrier for dissociation, imposing kinetic stabilization on TTR and preventing aggregation. This is an effective strategy to halt neurodegeneration associated with polyneuropathy, according to recent placebo-controlled clinical trial results. In three recent papers, we systematically ranked possibilities for the three substructures composing a typical TTR kinetic stabilizer, using fibril inhibition potency and plasma TTR binding selectivity data. Herein, we have successfully employed a substructure combination strategy to use these data to develop potent and selective TTR kinetic stabilizers that rescue cells from the cytotoxic effects of TTR amyloidogenesis. Of the 92 stilbene and dihydrostilbene analogues synthesized, nearly all potently inhibit TTR fibril formation. Seventeen of these exhibit a binding stoichiometry of >1.5 of a maximum of 2 to plasma TTR, while displaying minimal binding to the thyroid hormone receptor (<20%). Six analogues were definitively categorized as kinetic stabilizers by evaluating dissociation time-courses. High-resolution TTR.(kinetic stabilizer)(2) crystal structures (1.31-1.70 A) confirmed the anticipated binding orientation of the 3,5-dibromo-4-hydroxyphenyl substructure and revealed a strong preference of the isosteric 3,5-dibromo-4-aminophenyl substructure to bind to the inner thyroxine binding pocket of TTR.
Insights
Researchers developed new transthyretin (TTR) kinetic stabilizers to prevent TTR aggregation and associated amyloid diseases. These compounds stabilize TTR, halting neurodegeneration and rescuing cells from cytotoxic effects.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Neuroscience
Background:
- Transthyretin (TTR) aggregation causes amyloid diseases through proteotoxicity.
- TTR aggregation involves rate-limiting tetramer dissociation and monomer misfolding.
- Stabilizing the TTR tetramer is a strategy to prevent aggregation and neurodegeneration.
Purpose of the Study:
- To develop potent and selective TTR kinetic stabilizers using a substructure combination strategy.
- To identify compounds that prevent TTR aggregation and cellular toxicity.
Main Methods:
- Systematic ranking of TTR kinetic stabilizer substructures based on fibril inhibition and plasma TTR binding selectivity.
- Synthesis and screening of 92 stilbene and dihydrostilbene analogues.
- Evaluation of TTR binding stoichiometry, thyroid hormone receptor binding, and dissociation time-courses.
- High-resolution crystal structure determination of TTR-stabilizer complexes.
Main Results:
- Nearly all synthesized analogues potently inhibited TTR fibril formation.
- Seventeen analogues showed high binding stoichiometry to plasma TTR with minimal thyroid hormone receptor binding.
- Six analogues were confirmed as kinetic stabilizers.
- Crystal structures revealed specific binding interactions within the TTR thyroxine binding pocket.
Conclusions:
- A substructure combination strategy successfully yielded potent and selective TTR kinetic stabilizers.
- These novel compounds effectively rescue cells from TTR amyloidogenesis-induced cytotoxicity.
- The findings support the therapeutic potential of TTR kinetic stabilizers for amyloid diseases.
