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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...

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Autores principales: Hanada, Kentaro, Sakai, Shota, Kumagai, Keigo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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