Synthesis and structural analysis of halogen substituted fibril formation inhibitors of Human Transthyretin (TTR)

Ciccone, Lidia; Nencetti, Susanna; Rossello, Armando; Stura, E.A.; Orlandini, Elisabetta

doi:10.3109/14756366.2016.1167048

Cited by 15 publications

(20 citation statements)

References 49 publications

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“…According to the authors, this molecule represents an interesting scaffold. Moreover, the effect of the halogenation on the biological activity of previously reported TTR tetramer stabilizers has also been assayed to provide mechanistic insights into their binding properties [ 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Cotrina¹,

Oliveira

Leite

et al. 2020

IJMS

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Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers.

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Section: Introductionmentioning

confidence: 99%

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Cotrina¹,

Oliveira

Leite

et al. 2020

IJMS

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“…Nearly all ligands co‐crystallized with TTR were potent inhibitors of TTR fibril formation; their structures share the presence of two aromatic moieties (only recently have molecules with only one aromatic end group been crystallized), often bearing halogens, connected by a linker of different size. Many were NSAIDs, T 4 derivatives, benzoxazoles, biphenyls, oximes, estrogen analogues, or natural products.…”

Section: Resultsmentioning

confidence: 99%

“…Superpositiono f8 7T TR structures revealed differencesi n the side chain conformationo fr esidues Lys15, Thr119, Leu117, and Ser117;i np articular,t he Ser117 hydroxy group was found to be in different orientations due to coordinationt oasingle highly ordered water molecule, turning the oxygen atom toward the first or second binding site. [15] Nearly all ligands co-crystallized with TTR were potent inhibitors of TTR fibril formation; [16] their structuress hare the presence of two aromatic moieties (only recently have molecules with only one aromatic end group been crystallized), [17][18][19][20] often bearing halogens, connected by al inker of different size. Many wereN SAIDs, T 4 derivatives, benzoxazoles, biphenyls, oximes, estrogen analogues, or natural products.…”

Section: Dockingmentioning

confidence: 99%

Identification of Transthyretin Fibril Formation Inhibitors Using Structure‐Based Virtual Screening

Ortore

Martinelli

2017

ChemMedChem

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Transthyretin (TTR) is the primary carrier for thyroxine (T4) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study using crystal structures of wild‐type TTR was planned; our aim was to design new ligands that are able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the peculiarity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure‐based studies. Two docking steps, one that is very fast and a subsequent step that is more accurate, were used to screen the Aldrich Market Select database. Five compounds were selected, and their activity toward inhibiting TTR fibril formation was assessed. Three compounds were observed to be actives, two of which have the same potency as the positive control, and the other was found to be a promising lead compound. These results validate a computational protocol that is able to archive information on the key interactions between database compounds and TTR, which is valuable for supporting further studies.

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“…Familial amyloid polyneuropathy (FAP) is another TTR amyloidosis and is usually associate to Val30Met point mutation [106]. One therapeutic strategy against TTR amyloidosis is the tetramer stabilization by small molecules such as bisaryl [109,110] or monoaryl [111][112][113] structure-based compounds or natural molecules [114,115].…”

Section: Transthyretin (Ttr)mentioning

confidence: 99%

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

et al. 2020

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Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

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Synthesis and structural analysis of halogen substituted fibril formation inhibitors of Human Transthyretin (TTR)

Cited by 15 publications

References 49 publications

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Identification of Transthyretin Fibril Formation Inhibitors Using Structure‐Based Virtual Screening

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

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