Anti-Prion Activity of a Panel of Aromatic Chemical Compounds: In Vitro and In Silico Approaches

Ferreira, Natalia; Marques, Icaro A.; Conceição, Wesley A.; Macedo, Bruno; Machado, Clarice S C; Mascarello, Alessandra; Chiaradia-Delatorre, Louise Domeneghini; Yunes, Rosendo A.; Nunes, Ricardo José; Hughson, Andrew G.; Raymond, Lynne D.; Pascutti, Pedro Geraldo; Caughey, Byron; Cordeiro, Yraima

doi:10.1371/journal.pone.0084531

Cited by 42 publications

(49 citation statements)

References 54 publications

(74 reference statements)

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“…Although the end products of the reaction do not share all of the morphological and infectious properties of the input PrP Sc (25), the assay has been used to evaluate the efficacy of antiprion compounds (26). Using a modified version of RT-QuIC, we tested TUDCA's antiaggregation effect in the presence of infectious prions ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

Cortez

Campeau

Norman

et al. 2015

J Virol

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Prion diseases are fatal neurodegenerative disorders associated with the conversion of cellular prion protein (PrP C ) into its aberrant infectious form (PrP Sc ). There is no treatment available for these diseases. The bile acids tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) have been recently shown to be neuroprotective in other protein misfolding disease models, including Parkinson's, Huntington's and Alzheimer's diseases, and also in humans with amyotrophic lateral sclerosis. Here, we studied the therapeutic efficacy of these compounds in prion disease. We demonstrated that TUDCA and UDCA substantially reduced PrP conversion in cell-free aggregation assays, as well as in chronically and acutely infected cell cultures. This effect was mediated through reduction of PrP Sc seeding ability, rather than an effect on PrP C . We also demonstrated the ability of TUDCA and UDCA to reduce neuronal loss in prion-infected cerebellar slice cultures. UDCA treatment reduced astrocytosis and prolonged survival in RML prion-infected mice. Interestingly, these effects were limited to the males, implying a genderspecific difference in drug metabolism. Beyond effects on PrP Sc , we found that levels of phosphorylated eIF2␣ were increased at early time points, with correlated reductions in postsynaptic density protein 95. As demonstrated for other neurodegenerative diseases, we now show that TUDCA and UDCA may have a therapeutic role in prion diseases, with effects on both prion conversion and neuroprotection. Our findings, together with the fact that these natural compounds are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans, make these compounds promising alternatives for the treatment of prion diseases. IMPORTANCEPrion diseases are fatal neurodegenerative diseases that are transmissible to humans and other mammals. There are no diseasemodifying therapies available, despite decades of research. Treatment targets have included inhibition of protein accumulation, clearance of toxic aggregates, and prevention of downstream neurodegeneration. No one target may be sufficient; rather, compounds which have a multimodal mechanism, acting on different targets, would be ideal. TUDCA and UDCA are bile acids that may fulfill this dual role. Previous studies have demonstrated their neuroprotective effects in several neurodegenerative disease models, and we now demonstrate that this effect occurs in prion disease, with an added mechanistic target of upstream prion seeding. Importantly, these are natural compounds which are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans with primary biliary cirrhosis. They have recently been proven efficacious in human amyotrophic lateral sclerosis. Therefore, these compounds are promising options for the treatment of prion diseases. P rion diseases are fatal neurodegenerative diseases that include Creutzfeldt-Jakob disease in hum...

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Section: Resultsmentioning

confidence: 99%

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

Cortez

Campeau

Norman

et al. 2015

J Virol

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“…The 110 assayed synthetic compounds (Table S1, Supplementary information), were prepared as described in our previous reports [19][20][21][22][23][24][25][26][27][28][29] . Reagents were obtained from Sigma-Aldrich Õ (St. Louis, MO) and solvents from Vetec (Duque de Caxias, RJ, Brazil).…”

Section: Synthesis and Purification Of The Compoundsmentioning

confidence: 99%

“…The (E)-chalcones 1-82 were prepared by aldol condensation using methanol as solvent under basic conditions (KOH 50% w/v) at room temperature for 24 h. Distilled water and 10% hydrochloric acid were added to the reaction for total precipitation of the compounds, which were then obtained by vacuum filtration and later recrystallized in dichloromethane and hexane [20][21][22][23][24][25][26][27][28][29] . The (E)-N 0 -benzylidene-benzohydrazides 83-99 were synthesized by condensation of the benzohydrazide (2 mmol) or 3,4,5-trimethoxy-benzohydrazide (2 mmol), with the appropriate aldehyde (2 mmol) in methanol (15 mL) and refluxed for 2 h. After cooling, the crude product was collected by filtration, washed and recrystallized from hot ethanol to give white solids [20][21][22][23][24][25][26][27][28][29] .…”

Section: Synthesis and Purification Of The Compoundsmentioning

confidence: 99%

Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum

Bertoldo¹,

Chiaradia-Delatorre²,

Mascarello³

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkylesters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC 50 values (8.5 ± 0.8 mM, 9.5 ± 0.2 mM and 4.9 ± 1.3 mM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.

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“…Additional study is needed to establish the robustness of real-time conversion methodology when used with a variety of delivery solvents or compounds. However, the ease and highthroughput nature of RT-QuIC can facilitate widespread screening for molecules that inhibit prion amyloid formation (61).…”

Section: Figmentioning

confidence: 99%

Endogenous Brain Lipids Inhibit Prion Amyloid Formation In Vitro

Hoover

Davenport

Henderson

et al. 2017

J Virol

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The normal cellular prion protein (PrP C ) resides in detergent-resistant outer membrane lipid rafts in which conversion to the pathogenic misfolded form is believed to occur. Once misfolding occurs, the pathogenic isoform polymerizes into highly stable amyloid fibrils. In vitro assays have demonstrated an intimate association between prion conversion and lipids, specifically phosphatidylethanolamine, which is a critical cofactor in the formation of synthetic infectious prions. In the current work, we demonstrate an alternative inhibitory function of lipids in the prion conversion process as assessed in vitro by real-time quaking-induced conversion (RTQuIC). Using an alcohol-based extraction technique, we removed the lipid content from chronic wasting disease (CWD)-infected white-tailed deer brain homogenates and found that lipid extraction enabled RT-QuIC detection of CWD prions in a 2-log 10 -greater concentration of brain sample. Conversely, addition of brain-derived lipid extracts to CWD prion brain or lymph node samples inhibited amyloid formation in a dose-dependent manner. Subsequent lipid analysis demonstrated that this inhibitory function was restricted to the polar lipid fraction in brain. We further investigated three phospholipids commonly found in lipid membranes, phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol, and found all three similarly inhibited RT-QuIC. These results demonstrating polar-lipid, and specifically phospholipid, inhibition of prion-seeded amyloid formation highlight the diverse roles lipid constituents may play in the prion conversion process. IMPORTANCE Prion conversion is likely influenced by lipid interactions, given the location of normal prion protein (PrP C ) in lipid rafts and lipid cofactors generating infectious prions in in vitro models. Here, we use real-time quaking-induced conversion (RT-QuIC) to demonstrate that endogenous brain polar lipids can inhibit prionseeded amyloid formation, suggesting that prion conversion is guided by an environment of proconversion and anticonversion lipids. These experiments also highlight the applicability of RT-QuIC to identify potential therapeutic inhibitors of prion conversion.

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Anti-Prion Activity of a Panel of Aromatic Chemical Compounds: In Vitro and In Silico Approaches

Cited by 42 publications

References 54 publications

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum

Endogenous Brain Lipids Inhibit Prion Amyloid Formation In Vitro

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