Library Synthesis and Screening:  2,4-Diphenylthiazoles and 2,4-Diphenyloxazoles as Potential Novel Prion Disease Therapeutics

Heal, William P.; Thompson, Mark J.; Mutter, Roger; Cope, Hannah; Louth, Jenny C.; Chen, Beining

doi:10.1021/jm0612719

Cited by 42 publications

(35 citation statements)

References 20 publications

(28 reference statements)

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“…The density of PrP Sc derived from GTϩFK cells in each solution was measured and compared with that of the control treated with medium containing solvent. Compounds were judged to be effective if levels of PrP Sc were reduced to less than 70% of the control, as reported previously (8). At least two independent experiments were performed to determine the levels of PrP Sc .…”

Section: Methodsmentioning

confidence: 99%

Variety of Antiprion Compounds Discovered through an In Silico Screen Based on Cellular-Form Prion Protein Structure: Correlation between Antiprion Activity and Binding Affinity

Hosokawa-Muto

Kamatari

Nakamura

et al. 2009

Antimicrob Agents Chemother

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Transmissible spongiform encephalopathies are associated with the conformational conversion of the prion protein from the cellular form (PrP C ) to the scrapie form. This process could be disrupted by stabilizing the PrP C conformation, using a specific ligand identified as a chemical chaperone. To discover such compounds, we employed an in silico screen that was based on the nuclear magnetic resonance structure of PrP C . In combination, we performed ex vivo screening using the Fukuoka-1 strain-infected neuronal mouse cell line at a compound concentration of 10 M and surface plasmon resonance. Initially, we selected 590 compounds according to the calculated docked energy and finally discovered 24 efficient antiprion compounds, whose chemical structures are quite diverse. Surface plasmon resonance studies showed that the binding affinities of compounds for PrP C roughly correlated with the compounds' antiprion activities, indicating that the identification of chemical chaperones that bind to the PrP C structure and stabilize it is one efficient strategy for antiprion drug discovery. However, some compounds possessed antiprion activities with low affinities for PrP C , indicating a mechanism involving additional modulation factors. We classified the compounds roughly into five categories: (i) binding and effective, (ii) low binding and effective, (iii) binding and not effective, (iv) low binding and not effective, and (v) acceleration. In conclusion, we found a spectrum of compounds, many of which are able to modulate the pathogenic conversion reaction. The appropriate categorization of these diverse compounds would facilitate antiprion drug discovery and help to elucidate the pathogenic conversion mechanism.

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Section: Methodsmentioning

confidence: 99%

Variety of Antiprion Compounds Discovered through an In Silico Screen Based on Cellular-Form Prion Protein Structure: Correlation between Antiprion Activity and Binding Affinity

Hosokawa-Muto

Kamatari

Nakamura

et al. 2009

Antimicrob Agents Chemother

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“…[5] We previously reported the use of a scrapie mouse brain (SMB) cell line, [6,7] cloned from murine brain infected with the Chandler scrapie strain, in the identification of a number of active inhibitors of PrP Sc accumulation across four distinct structural classes: 9-aminoacridines and related compounds, [8] pyridine-3,5-dicarbonitriles, [9] indole-3-glyoxylamides, [10] and 2,4-diphenyl-thiazoles and oxazoles 1 (Figure 1). [11] Within the latter class, six moderately active compounds were identified, with EC 50 values ranging from 1.5-20 mm.…”

Section: Introductionmentioning

confidence: 99%

“…Owing to poor reproducibility of these compounds' antiprion effect across differing passage numbers, and also to clear cytotoxicity of trifluoroacetyl compounds 1 a and 1 b close to their active concentrations (EC 50~1 .5 mm; LD 50~5 mm), [11] analogues with improved potency and therapeutic window were sought. Considering possible modifications to 1 that might Amide derivatives of 2,4-diarylthiazole-5-carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease.…”

Section: Introductionmentioning

confidence: 99%

Improved 2,4‐Diarylthiazole‐Based Antiprion Agents: Switching the Sense of the Amide Group at C5 Leads to an Increase in Potency

et al. 2010

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Amide derivatives of 2,4-diarylthiazole-5-carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease. A number of compounds demonstrating antiprion activity were thereby identified from the screening libraries, showing improved potency and reproducibility of results relative to amide derivatives of the related 2,4-diphenyl-5-aminothiazole, which have been documented previously. Thus, 'switching' the sense of the amide bond at thiazole C5 revealed a more promising lead series of potential prion disease therapeutics. Furthermore, 3,5-diaryl-1,2,4-thiadiazoles isolated as by-products during library synthesis provided a handful of additional examples possessing an antiprion effect, thereby augmenting the set of newly identified active compounds. Evaluation of binding to cellular prion protein (PrP(C)) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrP(C).

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“…Drugs from various molecular families (such as polyanionic, tetrapyrrolic or tricyclic compounds, polyene antibiotics, tetracyclins, β-sheet breaker peptides, Congo red, and others) have been found to impede prion replication, but none of them are of practical use because of efficacy, pharmacology, or toxicity issues (6)(7)(8). Screening of compound libraries for antiprion therapeutics has been implemented by using PrP Sc -based assays (9)(10)(11)(12)(13)(14). Because PrP is essential for prion propagation, we decided to develop a procedure allowing high-throughput screening for drugs capable of reducing PrP expression.…”

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confidence: 99%

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

Karapetyan

Sferrazza

Zhou

et al. 2013

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

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Prion diseases such as Creutzfeldt-Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP-FRET-enabled high throughput assay (PrP-FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identified astemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells. Tacrolimus reduced total cellular PrP levels by a nontranscriptional mechanism. Astemizole stimulated autophagy, a hitherto unreported mode of action for this pharmacophore. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice. Astemizole is used in humans to treat seasonal allergic rhinitis in a chronic setting. Given the absence of any treatment option for CJD patients and the favorable drug characteristics of astemizole, including its ability to cross the bloodbrain barrier, it may be considered as therapy for CJD patients and for prophylactic use in familial prion diseases. Importantly, our results validate PrP-FEHTA as a method to identify antiprion compounds and, more generally, FEHTA as a unique drug discovery platform.protein misfolding | high-throughput screening | prion therapeutics

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Library Synthesis and Screening: 2,4-Diphenylthiazoles and 2,4-Diphenyloxazoles as Potential Novel Prion Disease Therapeutics

Cited by 42 publications

References 20 publications

Variety of Antiprion Compounds Discovered through an In Silico Screen Based on Cellular-Form Prion Protein Structure: Correlation between Antiprion Activity and Binding Affinity

Variety of Antiprion Compounds Discovered through an In Silico Screen Based on Cellular-Form Prion Protein Structure: Correlation between Antiprion Activity and Binding Affinity

Improved 2,4‐Diarylthiazole‐Based Antiprion Agents: Switching the Sense of the Amide Group at C5 Leads to an Increase in Potency

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

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