Nakao, Naoki Daiichi Sankyo RD Novare Co. Ltd.
Ueno, Masaharu the University of Tokyo|Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Sakai, Shota National Institute of Infectious Diseases
Egawa, Daichi National Institute of Infectious Diseases
Hanzawa, Hiroyuki Daiichi Sankyo RD Novare Co. Ltd.
Kawasaki, Shohei Daiichi Sankyo RD Novare Co. Ltd.
Kumagai, Keigo National Institute of Infectious Diseases
Suzuki, Makoto Daiichi Sankyo RD Novare Co. Ltd.
Kobayashi, Shu the University of Tokyo
Hanada, Kentaro National Institute of Infectious Diseases
Lipid transfer proteins mediate inter-organelle transport of membrane lipids at organelle contact sites in cells, playing fundamental roles in the lipidome and membrane biogenesis in eukaryotes. We previously developed a ceramide-mimetic compound as a potent inhibitor of the ceramide transport protein CERT. Here we develop CERT inhibitors with structures unrelated to ceramide. To this aim, we identify a seed compound with no ceramide-like structure but with the capability of forming a hydrogen-bonding network in the ceramide-binding START domain, by virtual screening of ~3 × 106 compounds. We also establish a surface plasmon resonance-based system to directly determine the affinity of compounds for the START domain. Then, we subject the seed compound to a series of in silico docking simulations, efficient chemical synthesis, affinity analysis, protein-ligand co-crystallography, and various in vivo assays. This strategy allows us to obtain ceramide-unrelated compounds that potently inhibited the function of CERT in human cultured cells.
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