Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration.
Hua LinJonathan Z LongAlexander M RocheKatrin J SvenssonFlorence Y DouMi Ra ChangTimothy StrutzenbergClaudia RuizMichael D CameronScott J NovickCharles A BerdanSharon M LouieDaniel K NomuraBruce M SpiegelmanPatrick R GriffinTheodore M KameneckaPublished in: Journal of medicinal chemistry (2018)
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.
Keyphrases
- adipose tissue
- amino acid
- fatty acid
- insulin resistance
- high fat diet induced
- molecular docking
- oxidative stress
- induced apoptosis
- nitric oxide synthase
- metabolic syndrome
- small molecule
- type diabetes
- weight loss
- cell death
- particulate matter
- air pollution
- high throughput
- blood pressure
- weight gain
- hydrogen peroxide
- reactive oxygen species
- risk assessment
- heavy metals
- physical activity
- body mass index
- nitric oxide
- cell proliferation
- single cell
- blood glucose