Abstract
Transthyretin is a homotetrameric protein that carries thyroxine and retinol binding protein in plasma and is associated with a variety of amyloid diseases. One approach to the potential treatment of TTR amyloidosis is the stabilization of the native tetramer, over the dissociative transition state, through the binding of small molecules; this increases the kinetic barrier for tetramer dissociation and prevents protein misfolding. Several molecules discovered through focused screening, or created utilizing the structure-based design, were studied to identify the structural features that could make up for a good candidate drug. In this review, we examine several different chemical classes of TTR fibril formation inhibitors, highlighting the structural modifications that have led to an improvement or to a decrease of their potency and/or selectivity.
Keywords: Transthyretin (TTR), TTR-amyloidosis, familial transthyretin amyloidosis (FAP, FAC, SSA), protein-misfolding disorders, TTR amyloid fibril formation inhibitors, structure based drug discovery, amyloid fibril formation inhibitors, SAR
Current Medicinal Chemistry
Title:TTR Fibril Formation Inhibitors: Is there a SAR?
Volume: 19 Issue: 15
Author(s): S. Nencetti, E. Orlandini
Affiliation:
Keywords: Transthyretin (TTR), TTR-amyloidosis, familial transthyretin amyloidosis (FAP, FAC, SSA), protein-misfolding disorders, TTR amyloid fibril formation inhibitors, structure based drug discovery, amyloid fibril formation inhibitors, SAR
Abstract: Transthyretin is a homotetrameric protein that carries thyroxine and retinol binding protein in plasma and is associated with a variety of amyloid diseases. One approach to the potential treatment of TTR amyloidosis is the stabilization of the native tetramer, over the dissociative transition state, through the binding of small molecules; this increases the kinetic barrier for tetramer dissociation and prevents protein misfolding. Several molecules discovered through focused screening, or created utilizing the structure-based design, were studied to identify the structural features that could make up for a good candidate drug. In this review, we examine several different chemical classes of TTR fibril formation inhibitors, highlighting the structural modifications that have led to an improvement or to a decrease of their potency and/or selectivity.
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Cite this article as:
S. Nencetti, E. Orlandini , TTR Fibril Formation Inhibitors: Is there a SAR?, Current Medicinal Chemistry 2012; 19 (15) . https://dx.doi.org/10.2174/092986712800269326
DOI https://dx.doi.org/10.2174/092986712800269326 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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