Characterising diflunisal as a transthyretin kinetic stabilizer at relevant concentrations in human plasma using subunit exchange

Tsai, Felix J.; Nelson, Luke T.; Kline, Gabriel M.; Jäger, Markus; Berk, John L.; Sekijima, Yoshiki; Powers, Evan T.

doi:10.1080/13506129.2022.2148094

Cited by 5 publications

(3 citation statements)

References 28 publications

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“…These included diflunisal, which was shown to bind to TTR tetramer with negative cooperativity (with values of 75 nM and 1500 nM for the dissociation constants from the first and second T 4 binding sites, respectively) [97]. In addition, diflunisal could inhibit tetramer dissociation and in vitro fibril formation of wild-type TTR, as well as of the most common disease-associated TTR variants (Val30Met, Val122Ile, Thr60Ala, Leu58His, and Ile84Ser) [126][127][128].…”

Section: Diflunisalmentioning

confidence: 99%

Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy

Girelli

Merlini

2022

IJMS

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The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy.

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Section: Diflunisalmentioning

confidence: 99%

Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy

Girelli

Merlini

2022

IJMS

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“…A first clinical trial of CRISPR/Cas9 has recently been performed with successful results in the reduction of TTR production in humans . Currently, work is ongoing to better diagnose patients early, to follow up and monitor the various available treatments, and to find improved small-molecule ligands as kinetic stabilizers. − …”

Section: Introductionmentioning

confidence: 99%

“… 9 Currently, work is ongoing to better diagnose patients early, to follow up and monitor the various available treatments, and to find improved small-molecule ligands as kinetic stabilizers. 10 − 14 …”

Section: Introductionmentioning

confidence: 99%

Binding of a Pyrene-Based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study

Thi Minh,

Begum,

Zhang

et al. 2023

J. Phys. Chem. B

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Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are transstilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR−ligand complexes.

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Diflunisal versus tafamidis on neuropathy and cardiomyopathy in hereditary transthyretin amyloidosis

Chao,

Tzeng,

Chiang

et al. 2024

Ann Clin Transl Neurol

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ObjectivesHereditary transthyretin (TTR) amyloidosis (ATTRv) is frequently complicated by polyneuropathy (ATTRv‐PN) and cardiomyopathy (ATTRv‐CM). The long‐term efficacy of diflunisal on both polyneuropathy and cardiomyopathy in ATTRv patients, especially those with non‐V30M genotypes, has not been fully investigated and compared with that of tafamidis.MethodsWe compared the structural and biochemical characteristics of A97S‐TTR complexed with tafamidis with those of diflunisal, and prospectively followed up and compared the progression of polyneuropathy and cardiomyopathy between ATTRv‐PN patients taking diflunisal and those taking tafamidis.ResultsBoth diflunisal and tafamidis effectively bind to the two thyroxine‐binding sites at the A97S‐TTR dimer–dimer interface and equally and almost sufficiently reduce amyloid fibril formation. Thirty‐five ATTRv‐PN patients receiving diflunisal and 22 patients receiving tafamidis were enrolled. Compared with no treatment, diflunisal treatment significantly delayed the transition of FAP Stage 1 to 2 and Stage 2 to 3 and decreased the deterioration in parameters of the ulnar nerve conduction study (NCS). The progression of FAP stage or NCS parameters did not differ between patients treated with diflunisal and those treated with tafamidis. Both diflunisal and tafamidis treatments significantly decreased radiotracer uptake on 99mTc‐PYP SPECT and stabilized cardiac wall thickness and blood pro‐B‐type natriuretic peptide levels. No significant adverse events occurred during diflunisal or tafamidis treatment.InterpretationsThe binding patterns of both tafamidis and diflunisal to A97S‐TTR closely resembled those observed in the wild type. Diflunisal can effectively delay the progression of polyneuropathy and cardiomyopathy with similar efficacy to tafamidis and may become a cost‐effective alternative treatment for late‐onset ATTRv‐PN.

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Characterising diflunisal as a transthyretin kinetic stabilizer at relevant concentrations in human plasma using subunit exchange

Cited by 5 publications

References 28 publications

Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy

Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy

Binding of a Pyrene-Based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study

Diflunisal versus tafamidis on neuropathy and cardiomyopathy in hereditary transthyretin amyloidosis

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