Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System

Zhiqiang Du*, Stephanie Valtierra, Luzivette Robles Cardona, Sara Fernandez Dunne, Chi Hao Luan, Liming Li

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Prion-like protein aggregation underlies the pathology of a group of fatal neurodegenerative diseases in humans, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy. At present, few high-throughput screening (HTS) systems are available for anti-prion small-molecule identification. Here we describe an innovative phenotypic HTS system in yeast that allows for efficient identification of chemical compounds that eliminate the yeast prion [SWI+]. We show that some identified anti-[SWI+] compounds can destabilize other non-[SWI+] prions, and their antagonizing effects can be prion- and/or variant specific. Intriguingly, among the identified hits are several previously identified anti-PrPSc compounds and a couple of US Food and Drug Administration-approved drugs for AD treatment, validating the efficacy of this HTS system. Moreover, a few hits can reduce proteotoxicity induced by expression of several pathogenic mammalian proteins. Thus, we have established a useful HTS system for identifying compounds that can potentially antagonize prionization and human proteinopathies.

Original languageEnglish (US)
Pages (from-to)1664-1680.e4
JournalCell Chemical Biology
Volume26
Issue number12
DOIs
StatePublished - Dec 19 2019

Fingerprint

Chemical compounds
Prions
Yeast
Screening
Yeasts
Throughput
Alzheimer Disease
Prion Diseases
Neurodegenerative diseases
Amyotrophic Lateral Sclerosis
United States Food and Drug Administration
Neurodegenerative Diseases
Parkinson Disease
Pathology
Proteins
Agglomeration
Molecules
Pharmaceutical Preparations

Keywords

  • Saccharomyces cerevisiae
  • amyloids
  • anti-prion compounds
  • high-throughput screening
  • neurodegenerative diseases
  • prion
  • protein aggregation
  • swi1
  • yeast

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Du, Zhiqiang ; Valtierra, Stephanie ; Cardona, Luzivette Robles ; Dunne, Sara Fernandez ; Luan, Chi Hao ; Li, Liming. / Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System. In: Cell Chemical Biology. 2019 ; Vol. 26, No. 12. pp. 1664-1680.e4.
@article{4e37632f53704dd4a8e99528074277bb,
title = "Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System",
abstract = "Prion-like protein aggregation underlies the pathology of a group of fatal neurodegenerative diseases in humans, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy. At present, few high-throughput screening (HTS) systems are available for anti-prion small-molecule identification. Here we describe an innovative phenotypic HTS system in yeast that allows for efficient identification of chemical compounds that eliminate the yeast prion [SWI+]. We show that some identified anti-[SWI+] compounds can destabilize other non-[SWI+] prions, and their antagonizing effects can be prion- and/or variant specific. Intriguingly, among the identified hits are several previously identified anti-PrPSc compounds and a couple of US Food and Drug Administration-approved drugs for AD treatment, validating the efficacy of this HTS system. Moreover, a few hits can reduce proteotoxicity induced by expression of several pathogenic mammalian proteins. Thus, we have established a useful HTS system for identifying compounds that can potentially antagonize prionization and human proteinopathies.",
keywords = "Saccharomyces cerevisiae, amyloids, anti-prion compounds, high-throughput screening, neurodegenerative diseases, prion, protein aggregation, swi1, yeast",
author = "Zhiqiang Du and Stephanie Valtierra and Cardona, {Luzivette Robles} and Dunne, {Sara Fernandez} and Luan, {Chi Hao} and Liming Li",
year = "2019",
month = "12",
day = "19",
doi = "10.1016/j.chembiol.2019.10.004",
language = "English (US)",
volume = "26",
pages = "1664--1680.e4",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "12",

}

Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System. / Du, Zhiqiang; Valtierra, Stephanie; Cardona, Luzivette Robles; Dunne, Sara Fernandez; Luan, Chi Hao; Li, Liming.

In: Cell Chemical Biology, Vol. 26, No. 12, 19.12.2019, p. 1664-1680.e4.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identifying Anti-prion Chemical Compounds Using a Newly Established Yeast High-Throughput Screening System

AU - Du, Zhiqiang

AU - Valtierra, Stephanie

AU - Cardona, Luzivette Robles

AU - Dunne, Sara Fernandez

AU - Luan, Chi Hao

AU - Li, Liming

PY - 2019/12/19

Y1 - 2019/12/19

N2 - Prion-like protein aggregation underlies the pathology of a group of fatal neurodegenerative diseases in humans, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy. At present, few high-throughput screening (HTS) systems are available for anti-prion small-molecule identification. Here we describe an innovative phenotypic HTS system in yeast that allows for efficient identification of chemical compounds that eliminate the yeast prion [SWI+]. We show that some identified anti-[SWI+] compounds can destabilize other non-[SWI+] prions, and their antagonizing effects can be prion- and/or variant specific. Intriguingly, among the identified hits are several previously identified anti-PrPSc compounds and a couple of US Food and Drug Administration-approved drugs for AD treatment, validating the efficacy of this HTS system. Moreover, a few hits can reduce proteotoxicity induced by expression of several pathogenic mammalian proteins. Thus, we have established a useful HTS system for identifying compounds that can potentially antagonize prionization and human proteinopathies.

AB - Prion-like protein aggregation underlies the pathology of a group of fatal neurodegenerative diseases in humans, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy. At present, few high-throughput screening (HTS) systems are available for anti-prion small-molecule identification. Here we describe an innovative phenotypic HTS system in yeast that allows for efficient identification of chemical compounds that eliminate the yeast prion [SWI+]. We show that some identified anti-[SWI+] compounds can destabilize other non-[SWI+] prions, and their antagonizing effects can be prion- and/or variant specific. Intriguingly, among the identified hits are several previously identified anti-PrPSc compounds and a couple of US Food and Drug Administration-approved drugs for AD treatment, validating the efficacy of this HTS system. Moreover, a few hits can reduce proteotoxicity induced by expression of several pathogenic mammalian proteins. Thus, we have established a useful HTS system for identifying compounds that can potentially antagonize prionization and human proteinopathies.

KW - Saccharomyces cerevisiae

KW - amyloids

KW - anti-prion compounds

KW - high-throughput screening

KW - neurodegenerative diseases

KW - prion

KW - protein aggregation

KW - swi1

KW - yeast

UR - http://www.scopus.com/inward/record.url?scp=85076358251&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076358251&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2019.10.004

DO - 10.1016/j.chembiol.2019.10.004

M3 - Article

C2 - 31668517

AN - SCOPUS:85076358251

VL - 26

SP - 1664-1680.e4

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9448

IS - 12

ER -