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Research ArticleDrug Discovery and Translational Medicine

Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains

Kurt Giles, David B. Berry, Carlo Condello, Ronald C. Hawley, Alejandra Gallardo-Godoy, Clifford Bryant, Abby Oehler, Manuel Elepano, Sumita Bhardwaj, Smita Patel, B. Michael Silber, Shenheng Guan, Stephen J. DeArmond, Adam R. Renslo and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics October 2015, 355 (1) 2-12; DOI: https://doi.org/10.1124/jpet.115.224659
Kurt Giles
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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David B. Berry
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Carlo Condello
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Ronald C. Hawley
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Alejandra Gallardo-Godoy
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Clifford Bryant
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Abby Oehler
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Manuel Elepano
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Sumita Bhardwaj
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Smita Patel
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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B. Michael Silber
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Shenheng Guan
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Stephen J. DeArmond
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Adam R. Renslo
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Stanley B. Prusiner
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco
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Abstract

Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold that almost doubled the incubation times in scrapie prion-infected, wild-type (wt) FVB mice when given in a liquid diet. Remarkably, oral prophylactic treatment with IND24 beginning 14 days prior to intracerebral prion inoculation extended survival from ∼120 days to over 450 days. In addition to IND24, we evaluated the pharmacokinetics and efficacy of five additional 2-AMTs; one was not followed further because its brain penetration was poor. Of the remaining four new 2-AMTs, IND114338 doubled and IND125 tripled the incubation times of RML-inoculated wt and Tg4053 mice overexpressing wt mouse prion protein (PrP), respectively. Neuropathological examination of the brains from untreated controls showed a widespread deposition of self-propagating, β-sheet-rich “scrapie” isoform (PrPSc) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrPSc and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrPSc accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrPSc that accumulated in their brainstems. Disappointingly, none of the four new 2-AMTs prolonged the lives of mice expressing a chimeric human/mouse PrP transgene inoculated with Creutzfeldt-Jakob disease prions.

Footnotes

    • Received March 24, 2015.
    • Accepted July 28, 2015.
  • ↵1 Current affiliation: Afferent Pharmaceutics, San Francisco, California.

  • ↵2 Current affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.

  • ↵3 Current affiliation: Reiley Pharmaceuticals, Inc., San Jose, California.

  • This work was supported by the National Institutes of Health National Institute on Aging [Grants AI064709, AG002132, AG010770, AG021601, AG031220, and NS080630] as well as by gifts from the Sherman Fairchild Foundation, Schott Foundation for Public Education, Rainwater Charitable Foundation, Mary Jane Brinton Fund, Dana Foundation (A121428), and G. Harold and Leila Y. Mathers Charitable Foundation.

  • dx.doi.org/10.1124/jpet.115.224659.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (1)
Journal of Pharmacology and Experimental Therapeutics
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1 Oct 2015
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Research ArticleDrug Discovery and Translational Medicine

Efficacy of 2-Aminothiazoles for PrP Prion Disease

Kurt Giles, David B. Berry, Carlo Condello, Ronald C. Hawley, Alejandra Gallardo-Godoy, Clifford Bryant, Abby Oehler, Manuel Elepano, Sumita Bhardwaj, Smita Patel, B. Michael Silber, Shenheng Guan, Stephen J. DeArmond, Adam R. Renslo and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 2-12; DOI: https://doi.org/10.1124/jpet.115.224659

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Research ArticleDrug Discovery and Translational Medicine

Efficacy of 2-Aminothiazoles for PrP Prion Disease

Kurt Giles, David B. Berry, Carlo Condello, Ronald C. Hawley, Alejandra Gallardo-Godoy, Clifford Bryant, Abby Oehler, Manuel Elepano, Sumita Bhardwaj, Smita Patel, B. Michael Silber, Shenheng Guan, Stephen J. DeArmond, Adam R. Renslo and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 2-12; DOI: https://doi.org/10.1124/jpet.115.224659
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