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J Med Chem. 2018 Apr 12;61(7):3224-3230. doi: 10.1021/acs.jmedchem.8b00029. Epub 2018 Mar 22.

Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration.

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Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States.
Department of Pathology , Stanford University School of Medicine , Stanford , California 94305 , United States.
Departments of Cancer Biology and Cell Biology , Dana-Farber Cancer Institute and Harvard Medical School , Boston , Massachusetts 02215 , United States.
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology , University of California Berkeley , Berkeley , California 94720 , United States.


N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice.

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