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Targeting transthyretin – X-ray crystallography and rational drug design

DOI: 10.3109/13506121003737419 DOI Help

Authors: S. Kolstoe (UCL) , A. Morrison (UCL) , A. Cobb (UCL) , A. Coyne (UCL) , G. Gill (UCL) , M. D. Smith (UCL) , S. V. Ley (UCL) , S. P. Wood (UCL) , M. B. Pepys (UCL)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Amyloid , VOL 17 (s1) , PAGES p102

State: Published (Approved)
Published: April 2010

Abstract: Transthyretin (TTR) amyloid fibrillogenesis involves tetramer dissociation followed by structural changes within the monomer that render the protein capable of misassembly to the crossed-b form of the fibre. Kelly has pioneered a therapeutic strategy using small molecule ligands that bind in the thyroxine binding pockets of TTR to stabilise the native homotetrameric assembly. We designed palindromic, bivalent bis-aryl halides targeting the hormone binding sites of TTR to investigate the hypothesis that cross-linked octamers or higher multimers might experience enhanced clearance rates and provide a viable route for depleting this amyloidogenic protein from the circulation. As the compound 2-(3,5- dichlorophenyl amino)benzoic acid was reported to be bound by TTR with the chlorine bearing ring oriented to the outer halogen pockets of the protein, we linked two of these dichloro-bisaryl headgroups through their chlorinated rings with a 11 carbon linker. X-ray analysis of a co-crystallised complex with TTR revealed that this compound was bound simultaneously in both thyroxine binding sites of a single tetramer, with a complex translational disorder accommodating excess linker length and allowing both inner and outer halogen sites to be visited by the chlorine atoms of the ligand. X-ray analysis of an isolated head group bound by TTR showed that, in contrast to published data, such compounds are preferentially bound with their chlorinated rings located in the inner halogen pockets of the TTR tetramer. Structure analysis of a second bivalent compound in complex with TTR, where the linker length was reduced to seven carbon atoms, showed a well-ordered complex with the halogens of both head groups positioned in the inner sites of the TTR tetramer and clear electron density for the hydrocarbon linker passing through the centre of the tetramer. In contrast to previously reported studies of bivalent TTR ligands, this compound is rapidly bound by native TTR in solution and is a promising platform for development of drugs to inhibit TTR amyloid fibril formation in vivo.

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography