New Series of Antiprion Compounds: Pyrazolone Derivatives Have the Potent Activity of Inhibiting Protease-Resistant Prion Protein Accumulation

Kimata, Ayako; Nakagawa, Hidehiko; Ohyama, Ryo; Fukuuchi, Tomoko; Ohta, Shigeru; Doh‐ura, Katsumi; Suzuki, Takayoshi; Miyata, Naoki

doi:10.1021/jm8000532

Cited by 11 publications

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“…Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1)(2)(3)(4)(5) or to confirm the proposed antiprion effects of compounds discovered by other means (6,7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in particular those causing human diseases.…”

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confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

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

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Quinacrine's ability to reduce levels of pathogenic prion protein (PrP Sc ) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP Sc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP Sc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP Sc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.prion therapeutics | prion enhancing drugs P rions are protein-based infectious agents that cause an increasing variety of fatal, infectious neurodegenerative disorders, frequently as epidemics. Variant Creutzfeldt-Jakob disease (CJD) resulting from bovine spongiform encephalopathy exemplifies prion zoonosis, and the continued, unpredictable emergence of additional epidemics in other species, particularly chronic wasting disease (CWD) in deer, elk, and moose, raises additional concerns. Its unprecedented contagious spread, widening host range, and conflicting evidence surrounding its zoonotic potential place CWD at the forefront of public health concerns. Although the notion, that prion replication occurs by corruption of host-encoded cellular prion protein (PrP C ) by abnormally conformed PrP Sc , is now widely accepted, the details of this mechanism remain enigmatic.Except under certain experimental conditions, treatments capable of arresting or of effectively modifying the course of disease do not exist for prion disorders. Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1-5) or to confirm the proposed antiprion effects of compounds discovered by other means (6, 7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in ...

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mentioning

confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

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

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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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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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“…1) [1]. On the other hand, pyrazine and pyrazole are both potent bioactive heterocycles present as the key structural core in many natural products and synthetic compounds possessing wide spread biological and medicinal applications [2][3][4][5][6][7][8][9][10][11][12][13]. Consequently, several attempts have been made to construct various hybrid bicyclic molecular scaffolds which contains the above pharmacophores fused with each other [14][15][16].…”

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confidence: 99%

Synthesis of Novel tricyclic pyrazolo(1,4)oxathiinopyrazines and Evaluation of Their Competency Towards the Inhibition of Lactate Dehydrogenase Activity-Inhibition of LDH Activity

et al. 2018

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We have evaluated the LDH inhibitory property of novel pyrazolo[4',3':5,6][1,4]oxathiino[2,3-b]pyrazine derivatives which have been synthesized from easily available starting materials through a one-pot protocol that offers the use of elemental sulfur as the sulfur source. These newly synthesized compounds may aid to drug development for neoplastic and non-neoplastic diseases characterized by increased glucose metabolism. Additionally, they may act as suitable starting materials which can be further structurally modified for the development of new LDH inhibitors with higher efficacy and specificity.

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New Series of Antiprion Compounds: Pyrazolone Derivatives Have the Potent Activity of Inhibiting Protease-Resistant Prion Protein Accumulation

Abstract: 1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan" should be added as the second to last of the affiliations.

Cited by 11 publications

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Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

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

Synthesis of Novel tricyclic pyrazolo(1,4)oxathiinopyrazines and Evaluation of Their Competency Towards the Inhibition of Lactate Dehydrogenase Activity-Inhibition of LDH Activity

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