ID 113055
Author
Nakao, Naoki Daiichi Sankyo RD Novare Co. Ltd.
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
Content Type
Journal Article
Description
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.
Journal Title
Communications Chemistry
ISSN
23993669
Publisher
Springer Nature
Volume
2
Start Page
20
Published Date
2019-02-20
Rights
© 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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language
eng
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departments
Science and Technology