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Antiprion compounds that reduce PrP(Sc) levels in dividing and stationary-phase cells

B Michael Silber1, Joel R Gever, Zhe Li

  • 1Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, United States; Department of Neurology, University of California, San Francisco, CA 94143, United States; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, United States.

Bioorganic & Medicinal Chemistry
|November 5, 2013
PubMed

Insights

Researchers screened over 100,000 compounds to find drugs that reduce abnormal prion protein (PrPSc) in cells. They identified promising chemical leads, including an indole compound, with potential for treating prion diseases.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Prion diseases involve the misfolding of cellular prion protein (PrPC) into an aberrant isoform (PrPSc).
  • Developing therapeutic strategies to reduce PrPSc levels is crucial for treating prion diseases.

Purpose of the Study:

  • To identify and confirm small molecule drug leads that reduce PrPSc levels in prion-infected mouse neuroblastoma cells.
  • To evaluate the potency and efficacy of identified compounds in both dividing and stationary-phase cells.

Main Methods:

  • High-throughput screening (HTS) of over 52,000 diverse small molecules in dividing ScN2a-cl3 cells and over 49,000 in stationary-phase cells.
  • Enzyme-linked immunosorbent assay (ELISA) was used for hit identification and confirmation.
  • Concentration-effect relationships were determined to establish EC50 values and assess cell viability.

Main Results:

  • 3100 HTS and 970 single point confirmed (SPC) hits were identified in dividing cells; 331 HTS and 55 SPC hits in stationary-phase cells.
  • Fourteen chemical leads were identified from dividing cells and three from stationary-phase cells.
  • Potent compounds with EC50 values <1 μM were identified, with one indole lead showing efficacy in both cell states.

Conclusions:

  • This study successfully identified numerous chemical leads with the potential to reduce PrPSc levels.
  • The findings provide a foundation for developing novel therapeutics against prion diseases.
  • A significant difference in hit rates between dividing and stationary-phase cells was observed, warranting further investigation.
Keywords:
Antiprion compoundsDividing and stationary-phase brain cellsPrP(Sc)

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