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The flavonoid luteolin, but not luteolin-7-o-glucoside, prevents a transthyretin mediated toxic response
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.ORCID-id: 0000-0002-9500-5917
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. (Sauer-Eriksson)
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
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2015 (Engelska)Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 5, artikel-id e0128222Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic properties that has been linked to the development of familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic amyloidosis. The in vivo role of TTR is associated with transport of thyroxine hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR is a rate-limiting step in the process of TTR amyloid formation, and ligands with the ability to bind within the thyroxin binding site (TBS) can stabilize the tetramer, a feature that is currently used as a therapeutic approach for FAP. Several different flavonoids have recently been identified that impair amyloid formation. The flavonoid luteolin shows therapeutic potential with low incidence of unwanted side effects. In this work, we show that luteolin effectively attenuates the cytotoxic response to TTR in cultured neuronal cells and rescues the phenotype of a Drosophila melanogaster model of FAP. The plant-derived luteolin analogue cynaroside has a glucoside group in position 7 of the flavone A-ring and as opposed to luteolin is unable to stabilize TTR tetramers and thus prevents a cytotoxic effect. We generated high-resolution crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in complex with luteolin. The results show that the A-ring of luteolin, in contrast to what was previously suggested, is buried within the TBS, consequently explaining the lack of activity from cynaroside. The flavonoids represent an interesting group of drug candidates for TTR amyloidosis. The present investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We also show an alternative orientation of luteolin within the TBS which could represent a general mode of binding of flavonoids to TTR and is of importance concerning the future design of tetramer stabilizing drugs.

Ort, förlag, år, upplaga, sidor
Public Library Science , 2015. Vol. 10, nr 5, artikel-id e0128222
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-103893DOI: 10.1371/journal.pone.0128222ISI: 000355187300089PubMedID: 26020516Scopus ID: 2-s2.0-84935005411OAI: oai:DiVA.org:umu-103893DiVA, id: diva2:816189
Forskningsfinansiär
VetenskapsrådetTillgänglig från: 2015-06-02 Skapad: 2015-06-02 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Ingår i avhandling
1. Selection of transthyretin amyloid inhibitors
Öppna denna publikation i ny flik eller fönster >>Selection of transthyretin amyloid inhibitors
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Amyloidosis is a group of clinical disorders caused by the aggregation of specific proteins into abnormal extracellular deposits. Today, 31 different proteins have been linked to amyloid diseases including transthyretin-related amyloidosis (ATTR). ATTR occurs through the aggregation of either wild-type plasma protein transthyretin (TTR) or a mutated form. TTR is a homotetramer that under normal circumstances functions as a carrier of thyroxine and retinol binding protein. The aggregation cascade requires dissociation of the tetramer into monomers, and preventing this dissociation represents a potential mode of intervention. Interestingly, small molecules, referred as kinetic stabilizers, can bind to TTR’s thyroxine-binding site (TBS) and such molecules are currently being used as a therapeutic approach to impair tetramer dissociation.

The efficacy of TTR stabilization is directly correlated to the binding affinity of the ligand to TBS. However, the binding of the ligand to TTR in vivo can be affected by other plasma components resulting in poor efficacy. Thus, the selectivity of ligands is an important parameter. We have designed an assay where the ability to stabilize TTR can be directly evaluated in plasma and we have investigated the stabilizing effect of nine potential TTR binders (Paper I). The results, surprisingly, revealed that the binding affinity of molecules has a poor correlation to its selectivity. However, the nature of protein-ligand complex formation can also be described by enthalpic (∆H) and entropic (∆S) energy contributions. ∆H represents the change in chemical bonds and frequently requires a higher order of orientation compared to the ∆S component, which mainly represents the hydrophobic effect via the exclusion of water. We hypothesized that ligands possessing high ΔH in binding to their co-partner would also be more specific in a complex environment such as plasma. By applying a thermodynamic analysis using isothermal titration calorimetry, we found that the selectivity in plasma correlates well with the ∆H contribution and might, therefore, be a better predictor for selectivity.

Luteolin was found to be a highly selective stabilizer of TTR and was investigated further (Paper II). The ligand displayed a significant rescuing effect in both cell culture and animal models. However, luteolin undergoes rapid enzymatic degradation in the liver and this impairs its use as a potential therapeutic drug. To attempt to circumvent this issue, we modified the most exposed hydroxyl group thus rendering the molecule inert towards glucuronidation (Paper III). The substitutions resulted in higher stability in the face of hepatic degradation molecules, but they also affected the selectivity in a negative manner.

The screening for new TTR stabilizers resulted in the discovery of tetrabromobisphenol A, which displayed a very high selectivity (Paper IV). This study also included a comparison with the drug Vyndaqel™ which currently is in clinically use, and showed how the dosage could be altered to acquire a better level of saturation and possibly also a better clinical effect.

Taken together we present new molecules with the ability to stabilize TTR, and these can serve as scaffolds for the design of new drugs. We present a method to measure the efficacy of a TTR-stabilizing drugs in a complex matrix and as well as a way to adjust the dosage of existing drugs. We also show that the selectivity of a drug is affected by the relative proportion of ∆H and ∆S, and this is of interest for drug design in general.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2016. s. 72
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1826
Nyckelord
Transthyretin, TTR, ATTR, TTR-stabilizing drugs, selectivity
Nationell ämneskategori
Annan medicinsk grundvetenskap
Forskningsämne
medicinsk biokemi
Identifikatorer
urn:nbn:se:umu:diva-123939 (URN)978-91-7601-528-5 (ISBN)
Disputation
2016-09-09, KB3A9, byggnad KBC, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-08-18 Skapad: 2016-07-06 Senast uppdaterad: 2021-12-20Bibliografiskt granskad

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Iakovleva, IrinaBegum, AfshanWalfridsson, MalinSauer-Eriksson, A ElisabethOlofsson, Anders

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