Evaluation of the antiprion activity of 6-aminophenanthridines and related heterocycles

Nguyen, Phuhai; Oumata, Nassima; Soubigou, Flavie; Evrard, Justine; Desban, Nathalie; Lemoine, Pascale; Bouaziz, Serge; Blondel, Marc; Voisset, Cécile

doi:10.1016/j.ejmech.2014.05.083

Cited by 14 publications

(20 citation statements)

References 25 publications

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“…En utilisant ce test, constitué de deux étapes successives basées respectivement sur les prions [PSI + ] et [URE3], nous avons criblé plus de 15 000 molécules et isolé des molécules actives contre les prions de levure. Ces molécules se sont ensuite avérées actives contre le prion de mammifère PrP Sc en culture cellulaire et aussi in vivo, dans un modèle murin de maladies à prion [15,[22][23][24][25][26]. Ainsi, des molécules peuvent être actives à travers les règnes contre tous (Figure 4).…”

Section: Revuesunclassified

Chémobiologie à l’happy hour

Voisset

Blondel

2014

Med Sci (Paris)

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Section: Revuesunclassified

Chémobiologie à l’happy hour

Voisset

Blondel

2014

Med Sci (Paris)

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“…Misfolding monomers would emerge weak interacting ensemble on their surface which comprises binding stabilizing sites. Occupancy of one of these binding sites with a kinetic stabilizer, a small hydrophobic molecule that binds misfoldeding monomers with high affinity would be sufficient to make the misfolding barrier insurmountable under physiological conditions, and precluding amyloidogenesis .…”

Section: General Introduction To Protein Misfolding and Aggregation/amentioning

confidence: 99%

“…All amyloid fibrils have characteristic elongated fibrillar morphology with a ß‐sheet‐rich structure. The formation of well‐ordered fibrillar protein deposits is common to a large group of amyloid associated disorders such as AD, PD, prion diseases, HD, and familial amyloidosis .…”

Section: General Introduction To Protein Misfolding and Aggregation/amentioning

confidence: 99%

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Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases

2016

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Protein misfolding and inclusion body formations are common events in neurodegenerative diseases characterized by deposition of misfolded proteins inside or outside of neurons, and are commonly referred to as "protein misfolding neurodegenerative diseases" (PMNDs). These phenotypically diverse but biochemically similar aggregates suggest a highly conserved molecular mechanism of pathogenesis. These challenges are magnified by presence of mutations that render individual proteins subject to misfolding and/or aggregation. Cell proteostasis network and molecular chaperoning are maintaining cell proteome to preserve the protein folding, refolding, oligomerization, or disaggregation, and play formidable tasks to maintain the health of organism in the face of developmental changes, environmental insults, and rigors of aging. Maintenance of cell proteome requires the orchestration of major pathways of the cellular proteostasis network (heat shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the endoplasmic reticulum). Proteostasis responses culminate in transcriptional and post-transcriptional programs that up-regulate the homeostatic mechanisms. Proteostasis is strongly influenced by the general properties of individual proteins for folding, misfolding, and aggregation. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We first try to introduce some new chemical approaches to prevent the misfolding or aggregation of specific proteins via direct binding interactions. We then start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organ proteostasis. © 2016 BioFactors, 43(6):737-759, 2017.

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“…Thus, curing a yeast prion may be easier than curing a mammalian prion, but the fundamentals learned about how yeast cells handle amyloid prions are already aiding in the understanding of amyloidoses in general. Screens for compounds effective at curing yeast prions have revealed some that appear to also cure mammalian prions in tissue culture cells (205).…”

Section: Yeast Prions As Models For Human Amyloidosesmentioning

confidence: 99%

Yeast Prions: Structure, Biology, and Prion-Handling Systems

Wickner

Shewmaker

Bateman

et al. 2015

Microbiol Mol Biol Rev

128

142

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SUMMARY A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein aggregates with β-strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants.

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Evaluation of the antiprion activity of 6-aminophenanthridines and related heterocycles

Cited by 14 publications

References 25 publications

Chémobiologie à l’happy hour

Chémobiologie à l’happy hour

Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases

Yeast Prions: Structure, Biology, and Prion-Handling Systems

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