cb9b00444_si_001.pdf (3.41 MB)
Nutrient-Based Chemical Library as a Source of Energy Metabolism Modulators
journal contribution
posted on 2019-08-25, 12:30 authored by Tomoyuki Furuta, Yuya Mizukami, Lisa Asano, Kenjiro Kotake, Slava Ziegler, Hiroki Yoshida, Mizuki Watanabe, Shin-ichi Sato, Herbert Waldmann, Makiya Nishikawa, Motonari UesugiCovalent
conjugates of multiple nutrients often exhibit greater
biological activities than each individual nutrient and more predictable
safety profiles than completely unnatural chemical entities. Here,
we report the construction and application of a focused chemical library
of 308 covalent conjugates of a variety of small-molecule nutrients.
Screening of the library with a reporter gene of sterol regulatory
element-binding protein (SREBP), a master regulator of mammalian lipogenesis,
led to the discovery of a conjugate of docosahexaenoic acid (DHA),
glucosamine, and amino acids as an inhibitor of SREBP (molecule 1, DHG). Mechanistic analyses indicate that molecule 1 impairs the SREBP activity by inhibiting glucose transporters
and thereby activating AMP-activated protein kinase (AMPK). Oral administration
of molecule 1 suppressed the intestinal absorption of
glucose in mice. These results suggest that such synthetic libraries
of nutrient conjugates serve as a source of novel chemical tools and
pharmaceutical seeds that modulate energy metabolism.