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Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT
Lipid transfer proteins (LTPs) are recognized as key players in the inter-organelle trafficking of lipids and are rapidly gaining attention as a novel molecular target for medicinal products. In mammalian cells, ceramide is newly synthesized in the endoplasmic reticulum (ER) and converted to sphingo...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875512/ https://www.ncbi.nlm.nih.gov/pubmed/35216212 http://dx.doi.org/10.3390/ijms23042098 |
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author | Hanada, Kentaro Sakai, Shota Kumagai, Keigo |
author_facet | Hanada, Kentaro Sakai, Shota Kumagai, Keigo |
author_sort | Hanada, Kentaro |
collection | PubMed |
description | Lipid transfer proteins (LTPs) are recognized as key players in the inter-organelle trafficking of lipids and are rapidly gaining attention as a novel molecular target for medicinal products. In mammalian cells, ceramide is newly synthesized in the endoplasmic reticulum (ER) and converted to sphingomyelin in the trans-Golgi regions. The ceramide transport protein CERT, a typical LTP, mediates the ER-to-Golgi transport of ceramide at an ER-distal Golgi membrane contact zone. About 20 years ago, a potent inhibitor of CERT, named (1R,3S)-HPA-12, was found by coincidence among ceramide analogs. Since then, various ceramide-resembling compounds have been found to act as CERT inhibitors. Nevertheless, the inevitable issue remains that natural ligand-mimetic compounds might directly bind both to the desired target and to various undesired targets that share the same natural ligand. To resolve this issue, a ceramide-unrelated compound named E16A, or (1S,2R)-HPCB-5, that potently inhibits the function of CERT has recently been developed, employing a series of in silico docking simulations, efficient chemical synthesis, quantitative affinity analysis, protein–ligand co-crystallography, and various in vivo assays. (1R,3S)-HPA-12 and E16A together provide a robust tool to discriminate on-target effects on CERT from off-target effects. This short review article will describe the history of the development of (1R,3S)-HPA-12 and E16A, summarize other CERT inhibitors, and discuss their possible applications. |
format | Online Article Text |
id | pubmed-8875512 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88755122022-02-26 Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT Hanada, Kentaro Sakai, Shota Kumagai, Keigo Int J Mol Sci Review Lipid transfer proteins (LTPs) are recognized as key players in the inter-organelle trafficking of lipids and are rapidly gaining attention as a novel molecular target for medicinal products. In mammalian cells, ceramide is newly synthesized in the endoplasmic reticulum (ER) and converted to sphingomyelin in the trans-Golgi regions. The ceramide transport protein CERT, a typical LTP, mediates the ER-to-Golgi transport of ceramide at an ER-distal Golgi membrane contact zone. About 20 years ago, a potent inhibitor of CERT, named (1R,3S)-HPA-12, was found by coincidence among ceramide analogs. Since then, various ceramide-resembling compounds have been found to act as CERT inhibitors. Nevertheless, the inevitable issue remains that natural ligand-mimetic compounds might directly bind both to the desired target and to various undesired targets that share the same natural ligand. To resolve this issue, a ceramide-unrelated compound named E16A, or (1S,2R)-HPCB-5, that potently inhibits the function of CERT has recently been developed, employing a series of in silico docking simulations, efficient chemical synthesis, quantitative affinity analysis, protein–ligand co-crystallography, and various in vivo assays. (1R,3S)-HPA-12 and E16A together provide a robust tool to discriminate on-target effects on CERT from off-target effects. This short review article will describe the history of the development of (1R,3S)-HPA-12 and E16A, summarize other CERT inhibitors, and discuss their possible applications. MDPI 2022-02-14 /pmc/articles/PMC8875512/ /pubmed/35216212 http://dx.doi.org/10.3390/ijms23042098 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Hanada, Kentaro Sakai, Shota Kumagai, Keigo Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT |
title | Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT |
title_full | Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT |
title_fullStr | Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT |
title_full_unstemmed | Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT |
title_short | Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT |
title_sort | natural ligand-mimetic and nonmimetic inhibitors of the ceramide transport protein cert |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875512/ https://www.ncbi.nlm.nih.gov/pubmed/35216212 http://dx.doi.org/10.3390/ijms23042098 |
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