TTR Fibril Formation Inhibitors: Is there a 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.
Keywords: SAR; TTR amyloid fibril formation inhibitors; TTR-amyloidosis; Transthyretin (TTR); amyloid fibril formation inhibitors; familial transthyretin amyloidosis (FAP, FAC, SSA); protein-misfolding disorders; structure based drug discovery
Document Type: Research Article
Affiliations: Dipartimento di Scienze Farmaceutiche, Universita di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Publication date: May 1, 2012
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