Synthesis of Analogues of Congo Red and Evaluation of Their Anti-Prion Activity

Sellarajah, Shane; Lekishvili, Tamuna; Bowring, Claire; Thompsett, Andrew R.; Rudyk, Hélène; Birkett, Christopher R.; Brown, David R.; Gilbert, Ian H.

doi:10.1021/jm049922t

Cited by 63 publications

(56 citation statements)

References 40 publications

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“…Over the past 10 years there have been various efforts to find out small compounds to reduce PrP Sc population. These include porphyrins (26,27), Congo red and its derivatives (28)(29)(30), acridine and phenothiazine derivatives (17,31,32), heparan sulfate (33), aminoglycan, and polyamines (34,35). Simultaneously, various technological developments have been reported including structure-based drug design (36) followed by the structure-activity relationship study (37), small interfering RNA (38), library screening (18), high-throughput screening (39), chimeric ligand approach (40), and so on.…”

Section: Discussionmentioning

confidence: 99%

Hot spots in prion protein for pathogenic conversion

Kuwata

Nishida

Matsumoto

et al. 2007

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

174

225

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Prion proteins are key molecules in transmissible spongiform encephalopathies (TSEs), but the precise mechanism of the conversion from the cellular form (PrP C ) to the scrapie form (PrP Sc ) is still unknown. Here we discovered a chemical chaperone to stabilize the PrP C conformation and identified the hot spots to stop the pathogenic conversion. We conducted in silico screening to find compounds that fitted into a ''pocket'' created by residues undergoing the conformational rearrangements between the native and the sparsely populated high-energy states (PrP*) and that directly bind to those residues. Forty-four selected compounds were tested in a TSE-infected cell culture model, among which one, 2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide, termed GN8, efficiently reduced PrP Sc . Subsequently, administration of GN8 was found to prolong the survival of TSE-infected mice. Heteronuclear NMR and computer simulation showed that the specific binding sites are the A-S2 loop (N159) and the region from helix B (V189, T192, and K194) to B-C loop (E196), indicating that the intercalation of these distant regions (hot spots) hampers the pathogenic conversion process. Dynamics-based drug discovery strategy, demonstrated here focusing on the hot spots of PrP C , will open the way to the development of novel anti-prion drugs.anti-prion compound ͉ binding sites ͉ chemical chaperone ͉ dynamicsbased drug discovery ͉ transmissible spongiform encephalopathy

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Section: Discussionmentioning

confidence: 99%

Hot spots in prion protein for pathogenic conversion

Kuwata

Nishida

Matsumoto

et al. 2007

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

174

225

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“…目标化合物在 20 μg/mL 的浓度下, 对 PTP1B 和 SHP2 进行初筛, 将抑制率高于 50%的化合物进行复筛, [16] : 灰白色固体, [18] [19] N,N'-二苯基对苯二甲酰胺(6a) [20] [24] : 灰白色固 …”

Section: 生物活性测试unclassified

Synthesis of Aromatic Amide Derivatives and Their Biological Evaluation against Protein Tyrosine Phosphatase 1B and Scr Homology-2 Domain Containing Protein Tyrosine Phosphatase-2

Wang¹,

Huan²,

Ya³

et al. 2016

Chin. J. Org. Chem.

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To explore the chemical space of protein tyrosine phosphatase 1B (PTP1B) inhibitors by changing bis-aromatic amide moiety into aromatic amide moiety, a series of aromatic amide derivatives were designed, synthesized and their biological activities were evaluated against PTP1B and Scr homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). Among them, compound 3c displayed moderate inhibitory activity with IC 50 of (5.13±0.21) μmol/L against PTP1B and showed two times selectivity for other related PTPs. Interestingly, compound 12 [IC 50 ＝(7.47±1.26) μmol/L] showed moderate inhibitory activity against SHP2 and 2-fold selectivity against PTP1B, T-cell protein tyrosine phosphatase (TCPTP) or Src homology-2 domain containing protein tyrosine phosphatase-1 (SHP1) respectively, and offered a novel scaffold to develop new SHP2 inhibitors.

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“…Since the initial report that Congo Red can inhibit accumulation of PrP res in infected neuroblastoma cells [27], there have been numerous studies on the effects of Congo Red or derivatives with improved properties in various prion-infected cultures [22,28,37,83,107,119,129]. Congo Red treatment induced a small delay of the disease onset (around 10%) in infected hamsters provided the treatment had started around the time of infection [60,107].…”

Section: Congo Redmentioning

confidence: 99%

Cell models of prion infection

Vilette

2007

Vet. Res.

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-Due to recent renewal of interest and concerns in prion diseases, a number of cell systems permissive to prion multiplication have been generated in the last years. These include established cell lines, neuronal stem cells and primary neuronal cultures. While most of these models are permissive to experimental, mouse-adapted strains of prions, the propagation of natural field isolates from sheep scrapie and chronic wasting disease has been recently achieved. These models have improved our knowledge on the molecular and cellular events controlling the conversion of the PrP C protein into abnormal isoforms and on the cell-to-cell spreading of prions. Infected cultured cells will also facilitate investigations on the molecular basis of strain identity and on the mechanisms that lead to neurodegeneration. The ongoing development of new cell models with improved characteristics will certainly be useful for a number of unanswered critical issues in the prion field.

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Synthesis of Analogues of Congo Red and Evaluation of Their Anti-Prion Activity

Cited by 63 publications

References 40 publications

Hot spots in prion protein for pathogenic conversion

Hot spots in prion protein for pathogenic conversion

Synthesis of Aromatic Amide Derivatives and Their Biological Evaluation against Protein Tyrosine Phosphatase 1B and Scr Homology-2 Domain Containing Protein Tyrosine Phosphatase-2

Cell models of prion infection

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