2. Academic Validation
  3. Identification of a Novel Oleic Acid Analog with Protective Effects in Multiple Cellular Models of Friedreich Ataxia

Identification of a Novel Oleic Acid Analog with Protective Effects in Multiple Cellular Models of Friedreich Ataxia

  • ACS Chem Neurosci. 2020 Sep 2;11(17):2535-2542. doi: 10.1021/acschemneuro.0c00323.
M Grazia Cotticelli 1 2,  Roberto Forestieri 3,  Shujuan Xia 1 2,  Sipak Joyasawal 4,  Taehee Lee 1 2,  Kexin Xu 4,  Amos B Smith Iii 3,  Donna M Huryn 3 4,  Robert B Wilson 1 2 5
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, Children's Hospital Philadelphia, Philadelphia, Pennsylvania 19104, United States.
  • 2 The Penn Medicine/CHOP Center of Excellence for Friedreich's Ataxia Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 3 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 4 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
  • 5 Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
PMID: 32786299 DOI: 10.1021/acschemneuro.0c00323
Abstract

Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder for which there is no cure or approved treatment. It is characterized by the loss or impaired activity of frataxin protein, which is involved in the biogenesis of iron-sulfur clusters. Our previous studies suggested that cell death in FRDA may involve Ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation. Based on reports that oleic acid acts as a Ferroptosis inhibitor, we evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. We identified a trifluoromethyl alcohol analog of oleic acid that was significantly more potent than oleic acid itself. Further evaluation indicated that the effects were stereoselective, although a specific molecular target has not yet been identified. This work provides a potential starting point for therapeutics to treat FRDA, as well as a valuable probe molecule to interrogate FRDA pathophysiology.

Keywords

Friedreich ataxia; carboxylic acid isostere; ferroptosis; lipid peroxidation; oleic acid; trifluoromethyl alcohol.

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