Native State Kinetic Stabilization as a Strategy To Ameliorate Protein Misfolding Diseases:  A Focus on the Transthyretin Amyloidoses

Johnson, Steven M.; Wiseman, R. Luke; Sekijima, Yoshiki; Green, Nora S.; Adamski‐Werner, Sara L.; Kelly, Jeffery W.

doi:10.1021/ar020073i

Cited by 265 publications

(279 citation statements)

References 69 publications

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“…Additionally, as Wu and coworkers have demonstrated, the use of scattering-based techniques [73], including X-ray / neutron scattering and light scattering, combined with theory and simulation should be very useful in the study of aggregation-prone IDPs. Several groups in the amyloid field are already pursuing these types of multi-faceted approaches [5,84,[94][95][96][97][98][99][100][101][102][103][104][105][106][107]. However, we remain blind to interactions and conformational fluctuations that occur at low concentrations.…”

Section: Tests Of the Predictions Made By Raos And Allegramentioning

confidence: 99%

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Pappu

Wang

Vitalis

et al. 2008

Archives of Biochemistry and Biophysics

159

172

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Protein aggregation is a commonly occurring problem in biology. Cells have evolved stress-response mechanisms to cope with problems posed by protein aggregation. Yet, these quality control mechanisms are overwhelmed by chronic aggregation-related stress and the resultant consequences of aggregation become toxic to cells. As a result, a variety of systemic and neurodegenerative diseases are associated with various aspects of protein aggregation and rational approaches to either inhibit aggregation or manipulate the pathways to aggregation might lead to an alleviation of disease phenotypes. To develop such approaches, one needs a rigorous and quantitative understanding of protein aggregation. Much work has been done in this area. However, several unanswered questions linger, and these pertain primarily to the actual mechanism of aggregation as well as to the types of intermolecular associations and intramolecular fluctuations realized at low protein concentrations. It has been suggested that the concepts underlying protein aggregation are similar to those used to describe the aggregation of synthetic polymers. Following this suggestion, the relevant concepts of polymer aggregation are introduced. The focus is on explaining the driving forces for polymer aggregation and how these driving forces vary with chain length and solution conditions. It is widely accepted that protein aggregation is a nucleation-dependent process. This view is based mainly on the presence of long times for the accumulation of aggregates and the elimination of these lag times with "seeds". In this sense, protein aggregation is viewed as being analogous to the aggregation of colloidal particles. The theories for polymer aggregation reviewed in this work suggest an alternative mechanism for the origin of long lag times in protein aggregation. The proposed mechanism derives from the recognition that polymers have unique dynamics that distinguish them from other aggregation-prone systems such as colloidal particles.

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Section: Tests Of the Predictions Made By Raos And Allegramentioning

confidence: 99%

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Pappu

Wang

Vitalis

et al. 2008

Archives of Biochemistry and Biophysics

159

172

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“…Mutated TTR causes familial amyloid polyneuropathy (FAP) and/or cardiomyopathy (FAC), depending on the identity of the mutation the patient has inherited. TTR deposits occur throughout the peripheral and autonomic nervous system, and accumulate in various organ systems, such as gastrointestinal tract, heart, and kidney 1. Over the years, numerous experimental techniques have been applied to the study of TTR and the misfolding that ultimately leads to the deposition of insoluble amyloid fibrils.…”

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confidence: 99%

“…In general, DTTR showed an approximately two‐fold higher fibril accumulation than HTTR. Dissociation of the tetrameric state is thought to be the rate‐limiting step for TTR amyloidogenesis 1. The tetramer stability of HTTR and DTTR was therefore examined as a function of pH (Figure 2 B,C).…”

mentioning

confidence: 99%

Impact of Deuteration on the Assembly Kinetics of Transthyretin Monitored by Native Mass Spectrometry and Implications for Amyloidoses

Yee

Moulin

Breteau³

et al. 2016

Angew Chem Int Ed

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It is well established that the formation of transthyretin (TTR) amyloid fibrils is linked to the destabilization and dissociation of its tetrameric structure into insoluble aggregates. Isotope labeling is used for the study of TTR by NMR, neutron diffraction, and mass spectrometry (MS). Here MS, thioflavin T fluorescence, and crystallographic data demonstrate that while the X‐ray structures of unlabeled and deuterium‐labeled TTR are essentially identical, subunit exchange kinetics and amyloid formation are accelerated for the deuterated protein. However, a slower subunit exchange is noted in deuterated solvent, reflecting the poorer solubility of non‐polar protein side chains in such an environment. These observations are important for the interpretation of kinetic studies involving deuteration. The destabilizing effects of TTR deuteration are rather similar in character to those observed for aggressive mutations of TTR such as L55P (associated with familial amyloid polyneuropathy).

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“…This research has been successful in identifying a wide variety of structurally diverse compounds that impart kinetic stabilization to tetrameric TTR (for a recent review, see ref. 31). However, many of the most promising compounds are known nonsteriodal antiinflammatory drugs (NSAIDs), such as flufenamic acid and diflunisal ( Fig.…”

mentioning

confidence: 99%

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Julius

Farha²,

Chiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

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Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The regioselectivity and ease of derivatization of carboranes allows for facile syntheses of a wide variety of novel structures. The steric bulk, rigidity, and ease of B-and C-derivatization and lack ofinteractions associated with hydrophobic carboranes may be exploited to enhance the selectivity of previously identified bioactive molecules. Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases. Previous investigations have identified a variety of nonsteroidal antiinflammatory drugs (NSAIDs) and structurally related derivatives that imbue kinetic stabilization to TTR, thus inhibiting its dissociative fragmentation and subsequent aggregation to form putative toxic amyloid fibrils. However, the cyclooxygenase (COX) activity associated with these pharmaceuticals may limit their potential as long-term therapeutic agents for TTR amyloid diseases. Here, we report the synthesis and evaluation of carborane-containing analogs of the promising NSAID pharmaceuticals previously identified. The replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity with the retention of similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluorophenyl]-1,7-dicarba-closo-dodecaborane, showed effectively no COX-1 or COX-2 inhibition at a concentration more than an order of magnitude larger than the concentration at which TTR dissociation is nearly completely inhibited. This specificity is indicative of the potential for the exploitation of the unique properties of carboranes as potent and selective pharmacophores.amyloid ͉ cyclooxygenase ͉ nonsteroidal antiinflammatory drug ͉ fibril T he dicarba-closo-dodecaboranes (carboranes) are icosahedral carbon-containing boron clusters with extraordinary characteristic properties (such as resistance to catabolism, kinetic inertness to reagents, strong hydrophobicity, and wellestablished chemistry) that afford the opportunity for their exploitation as novel hydrophobic pharmacophores. The three isomeric dicarbon carboranes, closo-1,2-C 2 B 10 H 12 , closo-1,7-C 2 B 10 H 12 , and closo-1,12-C 2 B 10 H 12 , commonly known as ortho-, meta-, and para-carborane, respectively, share approximately the same volume as a rotated phenyl ring. This, as well as their structural integrity, ease of substitution, and delocalized bonding, suggests their description as three-dimensional analogs of aromatic hydrocarbons (1), allowing their facile substitution for phenyl rings as rigid scaffolding in pharmacological agents. This rigid scaffolding can be easily and selectively derivatized through deprotonation of the slightly acidic C-H vertices by a strong base (alkyllithium reagents, Grignard reagents, etc.) affording a strongly nucleophilic carboranyl anion capable of reaction with a wide range of electrophiles, inclu...

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Native State Kinetic Stabilization as a Strategy To Ameliorate Protein Misfolding Diseases: A Focus on the Transthyretin Amyloidoses

Cited by 265 publications

References 69 publications

A polymer physics perspective on driving forces and mechanisms for protein aggregation

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Impact of Deuteration on the Assembly Kinetics of Transthyretin Monitored by Native Mass Spectrometry and Implications for Amyloidoses

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

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