S B Prusiner

University of California, San Francisco, San Francisco, California, United States

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Publications (557)4854.73 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Prions are proteins that adopt self-propagating aberrant folds. The self-propagating properties of prions are a direct consequence of their distinct structures, making the understanding of these structures and their biophysical interactions fundamental to understanding prions and their related diseases. The insolubility and inherent disorder of prions have made their structures difficult to study, particularly in the case of the infectious form of the mammalian prion protein PrP. Many investigators have therefore preferred to work with peptide fragments of PrP, suggesting that these peptides might serve as structural and functional models for biologically active prions. We have used x-ray fiber diffraction to compare a series of different-sized fragments of PrP, to determine the structural commonalities among the fragments and the biologically active, self-propagating prions. Although all of the peptides studied adopted amyloid conformations, only the larger fragments demonstrated a degree of structural complexity approaching that of PrP. Even these larger fragments did not adopt the prion structure itself with detailed fidelity, and in some cases their structures were radically different from that of pathogenic PrP(Sc). Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.
    Biophysical Journal 03/2015; 108(6):1548-54. DOI:10.1016/j.bpj.2015.01.008 · 3.83 Impact Factor
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    ABSTRACT: The phosphotungstate anion (PTA) is widely used to facilitate the precipitation of disease-causing prion protein (PrP(Sc)) from infected tissue for applications in structural studies and diagnostic approaches. However, the mechanism of this precipitation is not understood. In order to elucidate the nature of the PTA interaction with PrP(Sc) under physiological conditions, solutions of PTA were characterized by NMR spectroscopy at varying pH. At neutral pH, the parent [PW12O40](3-) ion decomposes to give a lacunary [PW11O39](7-) (PW11) complex and a single orthotungstate anion [WO4](2-) (WO4). To measure the efficacy of each component of PTA, increasing concentrations of PW11, WO4, and mixtures thereof were used to precipitate PrP(Sc) from brain homogenates of scrapie prion-infected mice. The amount of PrP(Sc) isolated, quantified by ELISA and immunoblotting, revealed that both PW11 and WO4 contribute to PrP(Sc) precipitation. Incubation with sarkosyl, PTA, or individual components of PTA resulted in separation of higher-density PrP aggregates from the neuronal lipid monosialotetrahexosylganglioside (GM1), as observed by sucrose gradient centrifugation. These experiments revealed that yield and purity of PrP(Sc) were greater with polyoxometalates (POMs), which substantially supported the separation of lipids from PrP(Sc) in the samples. Interaction of POMs and sarkosyl with brain homogenates promoted the formation of fibrillar PrP(Sc) aggregates prior to centrifugation, likely through the separation of lipids like GM1 from PrP(Sc). We propose that this separation of lipids from PrP is a major factor governing the facile precipitation of PrP(Sc) by PTA from tissue and might be optimized further for the detection of prions.
    ACS Chemical Biology 02/2015; 10(5). DOI:10.1021/cb5006239 · 5.36 Impact Factor
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    ABSTRACT: An increasing number of studies argues that self-propagating protein conformations (i.e., prions) feature in the pathogenesis of several common neurodegenerative diseases. Mounting evidence contends that aggregates of the amyloid-β (Aβ) peptide become self-propagating in Alzheimer's disease (AD) patients. An important characteristic of prions is their ability to replicate distinct strains, the biological information for which is enciphered within different conformations of protein aggregates. To investigate whether distinct strains of Aβ prions can be discerned in AD patients, we performed transmission studies in susceptible transgenic mice using brain homogenates from sporadic or heritable (Arctic and Swedish) AD cases. Mice inoculated with the Arctic AD sample exhibited a pathology that could be distinguished from mice inoculated with the Swedish or sporadic AD samples, which was judged by differential accumulation of Aβ isoforms and the morphology of cerebrovascular Aβ deposition. Unlike Swedish AD- or sporadic AD-inoculated animals, Arctic AD-inoculated mice, like Arctic AD patients, displayed a prominent Aβ38-containing cerebral amyloid angiopathy. The divergent transmission behavior of the Arctic AD sample compared with the Swedish and sporadic AD samples was maintained during second passage in mice, showing that Aβ strains are serially transmissible. We conclude that at least two distinct strains of Aβ prions can be discerned in the brains of AD patients and that strain fidelity was preserved on serial passage in mice. Our results provide a potential explanation for the clinical and pathological heterogeneity observed in AD patients.
    Proceedings of the National Academy of Sciences 06/2014; 111(28). DOI:10.1073/pnas.1408900111 · 9.81 Impact Factor
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    ABSTRACT: An increasing number of studies continue to show that the amyloid β (Aβ) peptide adopts an alternative conformation and acquires transmissibility; hence, it becomes a prion. Here, we report on the attributes of two strains of Aβ prions formed from synthetic Aβ peptides composed of either 40 or 42 residues. Modifying the conditions for Aβ polymerization increased both the protease resistance and prion infectivity compared with an earlier study. Approximately 150 d after intracerebral inoculation, both synthetic Aβ40 and Aβ42 prions produced a sustained rise in the bioluminescence imaging signal in the brains of bigenic Tg(APP23:Gfap-luc) mice, indicative of astrocytic gliosis. Pathological investigations showed that synthetic Aβ40 prions produced amyloid plaques containing both Aβ40 and Aβ42 in the brains of inoculated bigenic mice, whereas synthetic Aβ42 prions stimulated the formation of smaller, more numerous plaques composed predominantly of Aβ42. Synthetic Aβ40 preparations consisted of long straight fibrils; in contrast, the Aβ42 fibrils were much shorter. Addition of 3.47 mM (0.1%) SDS to the polymerization reaction produced Aβ42 fibrils that were indistinguishable from Aβ40 fibrils produced in the absence or presence of SDS. Moreover, the Aβ amyloid plaques in the brains of bigenic mice inoculated with Aβ42 prions prepared in the presence of SDS were similar to those found in mice that received Aβ40 prions. From these results, we conclude that the composition of Aβ plaques depends on the conformation of the inoculated Aβ polymers, and thus, these inocula represent distinct synthetic Aβ prion strains.
    Proceedings of the National Academy of Sciences 06/2014; 111(28). DOI:10.1073/pnas.1408968111 · 9.81 Impact Factor
  • Joel C Watts, Stanley B Prusiner
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    ABSTRACT: Prions are self-propagating protein conformations that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses.
    Journal of Biological Chemistry 05/2014; 289(29). DOI:10.1074/jbc.R114.550707 · 4.60 Impact Factor
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    ABSTRACT: Bank voles are uniquely susceptible to a wide range of prion strains isolated from many different species. To determine if this enhanced susceptibility to interspecies prion transmission is encoded within the sequence of the bank vole prion protein (BVPrP), we inoculated Tg(M109) and Tg(I109) mice, which express BVPrP containing either methionine or isoleucine at polymorphic codon 109, with 16 prion isolates from 8 different species: humans, cattle, elk, sheep, guinea pigs, hamsters, mice, and meadow voles. Efficient disease transmission was observed in both Tg(M109) and Tg(I109) mice. For instance, inoculation of the most common human prion strain, sporadic Creutzfeldt-Jakob disease (sCJD) subtype MM1, into Tg(M109) mice gave incubation periods of ∼200 days that were shortened slightly on second passage. Chronic wasting disease prions exhibited an incubation time of ∼250 days, which shortened to ∼150 days upon second passage in Tg(M109) mice. Unexpectedly, bovine spongiform encephalopathy and variant CJD prions caused rapid neurological dysfunction in Tg(M109) mice upon second passage, with incubation periods of 64 and 40 days, respectively. Despite the rapid incubation periods, other strain-specified properties of many prion isolates-including the size of proteinase K-resistant PrPSc, the pattern of cerebral PrPSc deposition, and the conformational stability-were remarkably conserved upon serial passage in Tg(M109) mice. Our results demonstrate that expression of BVPrP is sufficient to engender enhanced susceptibility to a diverse range of prion isolates, suggesting that BVPrP may be a universal acceptor for prions.
    PLoS Pathogens 04/2014; 10(4):e1003990. DOI:10.1371/journal.ppat.1003990 · 8.06 Impact Factor
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    ABSTRACT: PurposePrevious studies showed that lowering PrPC concomitantly reduced PrPSc in the brains of mice inoculated with prions. We aimed to develop assays that measure PrPC on the surface of human T98G glioblastoma and IMR32 neuroblastoma cells. Using these assays, we sought to identify chemical hits, confirmed hits, and scaffolds that potently lowered PrPC levels in human brains cells, without lethality, and that could achieve drug concentrations in the brain after oral or intraperitoneal dosing in mice. Methods: We utilized HTS ELISA assays to identify small compounds that lower PrPC levels by ⩾30% on the cell surface of human glioblastoma (T98G) and neuroblastoma (IMR32) cells. Results: From 44,578 diverse chemical compounds tested, 138 hits were identified by single point confirmation (SPC) representing 7 chemical scaffolds in T98G cells, and 114 SPC hits representing 6 scaffolds found in IMR32 cells. When the confirmed SPC hits were combined with structurally related analogs, >300 compounds (representing 6 distinct chemical scaffolds) were tested for dose-response (EC50) in both cell lines, only studies in T98G cells identified compounds that reduced PrPC without killing the cells. EC50 values from 32 hits ranged from 65 nM to 4.1 μM. Twenty-eight were evaluated in vivo in pharmacokinetic studies after a single 10 mg/kg oral or intraperitoneal dose in mice. Our results showed brain concentrations as high as 16.2 μM, but only after intraperitoneal dosing. Conclusions: Our studies identified leads for future studies to determine which compounds might lower PrPC levels in rodent brain, and provide the basis of a therapeutic for fatal disorders caused by PrP prions.
    Bioorganic & medicinal chemistry 03/2014; DOI:10.1016/j.bmc.2014.01.001 · 2.95 Impact Factor
  • Stanley B Prusiner
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    ABSTRACT: Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.
    Annual Review of Genetics 11/2013; 47:601-23. DOI:10.1146/annurev-genet-110711-155524 · 18.12 Impact Factor
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    ABSTRACT: Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson's disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83(+/+) mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83(+/-) mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83(+/-) mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83(+/-) mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83(+/+) mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.
    Proceedings of the National Academy of Sciences 11/2013; DOI:10.1073/pnas.1318268110 · 9.81 Impact Factor
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    ABSTRACT: There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt-Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt-Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration.
    Proceedings of the National Academy of Sciences 10/2013; 110(44). DOI:10.1073/pnas.1317164110 · 9.81 Impact Factor
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    ABSTRACT: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD). This NIH/National Institute on Aging-funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2. Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months. This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials. This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months.
    Neurology 10/2013; 81(23). DOI:10.1212/WNL.0b013e3182a9f3b4 · 8.30 Impact Factor
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    ABSTRACT: During prion diseases, a normally benign, host protein, denoted PrP(C), undergoes alternative folding into the aberrant isoform, PrP(Sc). We used ELISA to identify and confirm hits in order to develop leads that reduce PrP(Sc) in prion-infected dividing and stationary-phase mouse neuroblastoma (ScN2a-cl3) cells. We tested 52,830 diverse small molecules in dividing cells and 49,430 in stationary-phase cells. This led to 3100 HTS and 970 single point confirmed (SPC) hits in dividing cells, 331 HTS and 55 confirmed SPC hits in stationary-phase cells as well as 36 confirmed SPC hits active in both. Fourteen chemical leads were identified from confirmed SPC hits in dividing cells and three in stationary-phase cells. From more than 682 compounds tested in concentration-effect relationships in dividing cells to determine potency (EC50), 102 had EC50 values between 1 and 10μM and 50 had EC50 values of <1μM; none affected cell viability. We observed an excellent correlation between EC50 values determined by ELISA and Western immunoblotting for 28 representative compounds in dividing cells (R(2)=0.75; p <0.0001). Of the 55 confirmed SPC hits in stationary-phase cells, 23 were piperazine, indole, or urea leads. The EC50 values of one indole in stationary-phase and dividing ScN2a-cl3 cells were 7.5 and 1.6μM, respectively. Unexpectedly, the number of hits in stationary-phase cells was ∼10% of that in dividing cells. The explanation for this difference remains to be determined.
    Bioorganic & medicinal chemistry 09/2013; 21(24). DOI:10.1016/j.bmc.2013.09.022 · 2.95 Impact Factor
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    ABSTRACT: The only small-molecule compound demonstrated to substantially extend survival in prion-infected mice is a biaryl hydrazone termed "Compd B." However, the hydrazone moiety of Compd B results in toxic metabolites, making it a poor candidate for further drug development. We developed a pharmacophore model based on diverse antiprion compounds identified by high-throughput screening and based on this model, we generated biaryl amide analogs of Compd B. Medicinal chemistry optimization led to multiple compounds with increased potency, increased brain concentrations, and greater metabolic stability, indicating that they could be promising candidates for antiprion therapy. Replacing the pyridyl ring of Compd B with a phenyl group containing an electron-donating substituent increased potency, while adding an aryl group to the oxazole moiety increased metabolic stability. In addition, we applied bioluminescence imaging, previously shown to detect prion disease onset in live mice earlier than clinical signs, and demonstrated it was possible to predict drug efficacy in two lines of prion-infected transgenic mice expressing a luciferase reporter long before extension in survival could be measured.
    Journal of Pharmacology and Experimental Therapeutics 08/2013; 347(2). DOI:10.1124/jpet.113.205799 · 3.86 Impact Factor
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    ABSTRACT: The prion diseases caused by PrP(Sc), an alternatively folded form of the cellular prion protein (PrP(C)), are rapidly progressive, fatal, and untreatable neurodegenerative syndromes. We employed HTS ELISA assays to identify compounds that lower the level of PrP(Sc) in prion-infected mouse neuroblastoma (ScN2a-cl3) cells and identified a series of arylamides. SAR studies indicated that small amides with one aromatic, or heteroaromatic ring, on each side of the amide bond are of modest potency. Of note, benzamide (7), with an EC50 of 2200 nM, was one of only a few arylamide hits with a piperazine group on its aniline moiety. The basic piperazine nitrogen can be protonated at physiologic pH, improving solubility, and therefore we wanted to exploit this feature in our search for a drug candidate. An SAR campaign resulted in several key analogs, including a set with biaryl groups introduced on the carbonyl side for improved potency. Several of these biaryl analogs have submicromolar potency, with the most potent analog 17 having an EC50 = 22 nM. More importantly, 17 and several biarylamides (20, 24, 26, 27) were able to traverse the BBB and displayed excellent drug levels in the brains of mice following oral dosing. These biarylamides may represent good starting points for further lead optimization for the identification of potential drug candidates for the treatment of prion diseases.
    ACS Medicinal Chemistry Letters 07/2013; 4(7):647-650. DOI:10.1021/ml300454k · 3.07 Impact Factor
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    Alzheimer's and Dementia 07/2013; 9(4):P168. DOI:10.1016/j.jalz.2013.05.263 · 17.47 Impact Factor
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    ABSTRACT: During prion disease, cellular prion protein (PrPC) is refolded into a pathogenic isoform (PrPSc) that accumulates in the central nervous system and causes neurodegeneration and death. We used immunofluorescence, quantitative cryo-immunogold EM, and tomography to detect nascent, full-length PrPSc in the hippocampus of prion-infected mice from early preclinical disease stages onward. Comparison of uninfected and infected brains showed that sites containing full-length PrPSc could be recognized in the neuropil by bright spots and streaks of immunofluorescence on semi-thin (200-nm) sections, and by clusters of cryo-immunogold EM labeling. PrPSc was found mainly on neuronal plasma membranes, most strikingly on membrane invaginations and sites of cell-to-cell contact, and was evident by 65 days postinoculation, or 54% of the incubation period to terminal disease. Both axons and dendrites in the neuropil were affected. We hypothesize that closely apposed plasma membranes provide a favorable environment for prion conversion and intercellular prion transfer. Only a small proportion of clustered PrP immunogold labeling was found at synapses, indicating that synapses are not targeted specifically in prion disease.
    Neurobiology of aging 06/2013; 34(6):1621-1631. DOI:10.1016/j.neurobiolaging.2012.12.015 · 4.85 Impact Factor
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    ABSTRACT: Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ~40 %, and high exposure in the brains of mice. Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrP(Sc) . Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties. Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1.
    ChemMedChem 05/2013; 8(5). DOI:10.1002/cmdc.201300007 · 3.05 Impact Factor
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    ABSTRACT: Prion diseases are a group of fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD) and kuru in humans, BSE in cattle, and scrapie in sheep. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrP(Sc)) of a normally benign, host cellular protein, denoted PrP(C). We employed high-throughput screening (HTS) ELISAs to evaluate compounds for their ability to reduce the level of PrP(Sc) in Rocky Mountain Laboratory (RML) prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identified but the initial hits suffered from low potency and poor drug-likeness. The best of those hits, such as 1, 7, 13, and 19, displayed moderate antiprion activity with EC50 values in the micromolar range. Key analogs were designed and synthesized based on the SAR, with analogs 41, 44, 46, and 47 found to have sub-micromolar potency. Analogs 41 and 44 were able to penetrate the blood-brain barrier (BBB) and achieved excellent drug concentrations in the brains of mice after oral dosing. These compounds represent good starting points for further lead optimization in our pursuit of potential drug candidates for the treatment of prion diseases.
    ACS Medicinal Chemistry Letters 04/2013; 4(4):397-401. DOI:10.1021/ml300472n · 3.07 Impact Factor
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    ABSTRACT: Prion diseases are neurodegenerative disorders characterized by the aberrant folding of endogenous proteins into self-propagating pathogenic conformers. Prion disease can be initiated in animal models by inoculation with amyloid fibrils formed from bacterially derived recombinant prion protein. The synthetic prions that accumulated in infected organisms are structurally distinct from the amyloid preparations used to initiate their formation and change conformationally on repeated passage. To investigate the nature of synthetic prion transformation, we infected mice with a conformationally diverse set of amyloids and serially passaged the resulting prion strains. At each passage, we monitored changes in the biochemical and biological properties of the adapting strain. The physicochemical properties of each synthetic prion strain gradually changed on serial propagation until attaining a common adapted state with shared physicochemical characteristics. These results indicate that synthetic prions can assume multiple intermediate conformations before converging into one conformation optimized for in vivo propagation.
    American Journal Of Pathology 03/2013; 182(3):866-74. DOI:10.1016/j.ajpath.2012.11.038 · 4.60 Impact Factor

Publication Stats

55k Citations
4,854.73 Total Impact Points


  • 1976–2015
    • University of California, San Francisco
      • • Institute for Neurodegenerative Diseases
      • • Department of Neurology
      • • Department of Biochemistry and Biophysics
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2009
    • Mount Sinai School of Medicine
      • Department of Neurology
      Manhattan, NY, United States
  • 1991–2008
    • Heinrich-Heine-Universität Düsseldorf
      • Institute of Physical Biology
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2007
    • European Commission - Joint Research Centre
      • Institute for Reference Materials and Measurements
      Brussels, BRU, Belgium
  • 1996–2006
    • CSU Mentor
      • Department of Neurology
      Long Beach, California, United States
  • 2004
    • University of Toronto
      Toronto, Ontario, Canada
  • 1997–2003
    • University of California, Santa Cruz
      • Department of Chemistry & Biochemistry
      Santa Cruz, CA, United States
  • 2002
    • Gifu University
      • School of Medicine
      Gihu, Gifu, Japan
  • 1999–2001
    • University of Oxford
      • Department of Biochemistry
      Oxford, ENG, United Kingdom
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
  • 2000
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 1998
    • Institute of Biochemistry and Biophysics
      Teheran, Tehrān, Iran
  • 1987–1998
    • University of California, Berkeley
      • School of Public Health
      Berkeley, California, United States
    • San Diego Zoo
      San Diego, California, United States
  • 1989–1997
    • McLaughlin Research Institute
      Great Falls, Montana, United States
  • 1993–1996
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, California, United States
  • 1990–1996
    • Hadassah Medical Center
      • Department of Neurology
      Jerusalem, Jerusalem District, Israel
    • University of Washington Seattle
      • Department of Pathology
      Seattle, WA, United States
  • 1988–1989
    • The Jackson Laboratory
      Bar Harbor, Maine, United States
  • 1984
    • Orlando Health
      Orlando, Florida, United States
    • California Institute of Technology
      • Division of Biology
      Pasadena, California, United States
  • 1980–1981
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 1978
    • Hamilton College
      Клинтон, New York, United States