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Complex with dibenzofuran-4,6-dicarboxylic acid

The TTR complexed with dibenzofuran-4,6-dicarboxylic acid has been produced from homo sapiens gene in Escherichia coli and it structure determined by X-Ray diffraction ([1]).

The dimer interface of the TTR is divided in two part, the inner and the outer binding cavity. The channel forming by dimerization has three symmetric binding pockets on each dimer parts. These pockets are called Halogen-binding pocket (HBPs) due to their ability to bind the iodines of thyroxine [3]. In the outer cavity are positioned the HBP1 and HBP1’ pockets, in the inner cavity are placed the HBP3 and HBP3’ pockets, and the HBP2 and HBP2’ pockets are at the interface between the inner and outer cavity

DDBF is bounded according two symmetric equivalent modes [2]. Indeed, DDBF wears a tricyclic ring system, with 2 hydrogen bond donors and 5 hydrogen bond acceptors, allowing to bound the dimer-dimer interface of the TTR cavity. [Pubchem,1]. Thanks to the complementarity of shape and hydrophobicity, DDBF enters nicely the outer portion of HBPs pockets [2]. Besides, the tricyclic ring system interacts with Lys15, Val17 and Ala108 from two adjacent TTR subunits [2]. Additionally, carboxylates at the position 4 and 6 of DDBF make electrostatic interactions at the entrance of HBP1 and HBP1’ with Lys15 on the ε-NH3+ groups[2].

1 TTR in complexe with Dibenzofuran-4,6-dicarboxylic acid (DDBF) TTR in complex with dibenzofuran-4,6-dicarboxylic acid keeps the general apo-structure, with water molecules bind to HBP3 and HBP3’ cavities of TTR [1]. There is not conformational change of Ser117 and Thr119 of TTR, contrary to other inhibitor, such as FLU. Consequently, DDBF creates a bridge between two adjacent subunits stabilized by ionic and hydrophobic interactions.

Improvements

To exploit the TTR inner cavity, DDBR can be ameliorate [1]. An additional substituent like an aryl ring could be link at DDBR thought a heteroatom or directly via a covalent bond [2]. For example, a N-phenyl phenoxazine-4,6-dicarboxylate, called Phenox (1dvy), allows to create additional bonds, which increase the kinetic stabilization of TTR. Besides, Van der Waals interactions are established with Thr106, Lys15, Leu17 from to adjacent TTR subunits. Moreover, the carboxylate groups link not only Lys15 but also Glu54 (carboxylate groups must to be protonated at physiological pH). In the side chain Leu17, Leu110 and Thr119 hydrophobic interactions take place with the trifluoromethyl group [1]. Unlike to a single DDBR, these substituted molecules make conformational change on side chains Thr119 and Ser117 with the formation of additional hydrogen bond. Furthermore, the water molecule in HBP3 pocket is displaced. [1] Advantages The substituted DDBR possess numerous advantages. In vivo, at a molar ratio of 1, there is more of 50% of fibril inhibition activity [3]. The occupancy of the TTR and the energetically favourable interactions reduce tetrameric dissociation by 70% [3]. In vitro, the tetrameric structure of TTR is retained during 7 days with the N-phenyl phenoxazine-4,6-dicarboxylate, whereas without inhibitor TTR fibril formation takes place after 72h. [1] Additionally, these drugs don’t affect the cyclooxygenase activities [3]. Consequently, DDBR and its derivatives are potent drug for human transthyretin amyloid disease.

References

[1] Sacchettini JC, Klabunde T, Petrassi HM, Oza VB, Raman P, Kelly JW. Rational design of potent human transthyretin amyloid disease inhibitors. Nature Structural Biology. April 2000 7(4):312-321. PMID:10742177 DOI:10.1038/74082

^[1]

[2] Johnson SM, Purkey HE, Chiang KP, Walkup T, Jiang X, Powers ET, Kelly JW. Potent and selective structure-based dibenzofuran inhibitors of transthyretin amyloidogenesis: kinetic stabilization of the native state. Journal of the American Chemical Society. May 2005 127(18):6662-6671. PMID :15869287 DOI:10.1021/ja044351f [3] Labaudinière R. Chapter 9 Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy. Orphan Drugs and Rare Diseases. Aug 2014 202-229. DOI :10.1039/9781782624202-00202 [Pubchem] National Center for Biotechnology Information. PubChem Database. CID:3022, https://pubchem.ncbi.nlm.nih.gov/compound/Dibenzofuran-4_6-dicarboxylic-acid (accessed on Dec. 26, 2019)