Abstract
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.
Highlights
Lipids are the major constituents of all cell membranes and play dynamic roles in organelle structure and function
Lipids newly synthesized in the endoplasmic reticulum (ER) are rapidly and accurately delivered to other organelles by a variety of lipid transfer proteins (LTPs), in a nonvesicular manner, at zones where the ER is in contact with other specific organelles [1,2,3,4,5,6]
The establishment of a set of ligand-mimetic and nonmimetic inhibitors has provided a pharmacological tool to discriminate on-target effects from offtarget effects. In this short review article, we describe the CERT inhibitors for which activity has been validated within living cells; we discuss possible medical applications of CERT inhibitors
Summary
Lipids are the major constituents of all cell membranes and play dynamic roles in organelle structure and function. Sci. 2022, 23, 2098 serendipitously developed [26]; it was later shown to be a selective inhibitor of CERT [27], as described in more detail below This ceramide-mimetic inhibitor of CERT has been widely used as a pharmacological tool in laboratory-based studies. The establishment of a set of ligand-mimetic and nonmimetic inhibitors has provided a pharmacological tool to discriminate on-target effects from offtarget effects. In this short review article, we describe the CERT inhibitors for which activity has been validated within living cells; we discuss possible medical applications of CERT inhibitors
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