開催日: 2017/09/20 - 2017/09/22
Covalent conjugates of nutrients including sugars, amino acids, fatty acids, and vitamins represent a recently emerging class of medicines and supplements. Such conjugates are also present endogenously in our body, exerting a myriad of biological activities. These “nutrient conjugates” tend to have two interesting properties: (i) potential to exert biological activity that individual nutrients are unable to generate; (ii) higher safety profiles as they are composed of endogenous nutrients. In this study, we constructed a conceptually new chemical library of “nutrient conjugates,” a systematic collection of covalently coupled multiple nutrients. The library was subjected to a number of cell-based screenings, and subsequently, we isolated the nutrient conjugates that inhibited SREBP (sterol regulatory element-binding protein), a transcription factor that orchestrates lipid synthesis and metabolism. Mechanistic analysis of one of the careening hits, referred to E2, indicated that E2 inhibits SREBP by inhibiting glucose transport and subsequent activation of AMPK (AMP-activated protein kinase). Moreover, E2 inhibited the increase in blood glucose level after glucose load in mice. Nutrient conjugate libraries might prove to be a rich source of medicines, supplements, and chemical tools for biology with a number of biological activities including energy metabolism.