A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity

Sungwook Choi, Natàlia Reixach, Stephen Connelly, Steven Johnson, Ian A. Wilson, Jeffery W. Kelly

Research output: Contribution to journalArticle

55 Citations (Scopus)

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-β-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 Å) 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.

Original languageEnglish (US)
Pages (from-to)1359-1370
Number of pages12
JournalJournal of the American Chemical Society
Volume132
Issue number4
DOIs
StatePublished - Feb 3 2010
Externally publishedYes

Fingerprint

Prealbumin
Cytotoxicity
Kinetics
Agglomeration
Stabilization
Plasmas
Amyloid
Stoichiometry
Monomers
Crystal structure
Thyroid Hormone Receptors
Stilbenes
Molecules
Polyneuropathies
Controlled Clinical Trials
Thyroxine
Placebos

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity. / Choi, Sungwook; Reixach, Natàlia; Connelly, Stephen; Johnson, Steven; Wilson, Ian A.; Kelly, Jeffery W.

In: Journal of the American Chemical Society, Vol. 132, No. 4, 03.02.2010, p. 1359-1370.

Research output: Contribution to journalArticle

Choi, Sungwook ; Reixach, Natàlia ; Connelly, Stephen ; Johnson, Steven ; Wilson, Ian A. ; Kelly, Jeffery W. / A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity. In: Journal of the American Chemical Society. 2010 ; Vol. 132, No. 4. pp. 1359-1370.
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