Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story

Burton, Arianna; Castaño, Adam; Bruno, Marianna; Riley, Steve; Schumacher, Jennifer; Sultan, Marla B.; Tai, Sandi See; Judge, Daniel P.; Patel, Jignesh

doi:10.2147/dddt.s289772

Cited by 40 publications

(30 citation statements)

References 117 publications

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“…45 Looking forward, it may become possible to pursue a drug discovery strategy for disordered proteins based on the stabilization of their native states through the disordered binding mechanism that we have described here. This strategy would extend an approach to disordered proteins that has already proven successful for folded proteins 46 and would have the advantage of maintaining the proteins in their native functional states.…”

Section: ■ Discussionmentioning

confidence: 99%

A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide

Löhr

Kohlhoff

Heller

et al. 2022

ACS Chem. Neurosci.

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The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer’s disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilize disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.

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Section: ■ Discussionmentioning

confidence: 99%

A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide

Löhr

Kohlhoff

Heller

et al. 2022

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Looking forward, it may become possible to pursue a drug discovery strategy for disordered proteins based on the stabilisation of their native states through the disordered binding mechanism that we have described here. This strategy would extend an approach to disordered proteins that has already proven successful for folded proteins [46], and would have the advantage of maintaining the proteins in their native functional states.…”

Section: Discussionmentioning

confidence: 99%

A small molecule stabilises the disordered native state of the Alzheimer’s Aβ peptide

Löhr

Kohlhoff

Heller

et al. 2021

Preprint

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The stabilisation of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here we report a small molecule that stabilises the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer’s disease. We show that this stabilisation takes place by a dynamic binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favourable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilise disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.

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“…TAF is administered orally, 20 mg once daily in polyneuropathy cases and 80 mg/61 mg once daily in cardiomyopathy ones, according to FDA [12][13][14]. The small molecule of TAF achieves high oral bioavailability, while there is no adverse side activity of NSAIDs [12].…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

A Brief Review of Analytical Methods for the Estimation of TTR Kinetic Stabilizers in Pharmaceutical Formulations and Biological Matrices

2022

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Transthyretin kinetic stabilizers are used as first-line drug therapy for transthyretin amyloid polyneuropathy mostly in patients unsuitable for liver transplantation. The two drugs prescribed in clinical practice are Tafamidis and Diflunisal. The European Medicines Agency approved Tafamidis for this prescription in 2011 and 2019 American Food and Drug Association also registered it for the same use. Diflunisal is a non-steroidal anti-inflammatory drug but its structural similarities to Tafamidis determine its “off-label” use for such clinical conditions. This review article represents the various analytical methods available in published literature for the determination of Tafamidis and Diflunisal in bulk drugs, pharmaceutical formulations, and biological matrices. Detailed information about all developed quantitative methods consisting of spectrophotometry, spectrofluorimetry, high-performance liquid chromatography with ultraviolet, fluorescence or diode array detection, liquid chromatography-tandem mass spectrometry, and voltammetry is provided and can be effectively used in the development of new analytical procedures and routine drug manufacturing or clinical practice.

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Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story

Cited by 40 publications

References 117 publications

A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide

A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide

A small molecule stabilises the disordered native state of the Alzheimer’s Aβ peptide

A Brief Review of Analytical Methods for the Estimation of TTR Kinetic Stabilizers in Pharmaceutical Formulations and Biological Matrices

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