Iminosugar-based ceramide mimicry for the design of new CERT START domain ligands

Santos, Cécile; Stauffert, Fabien; Ballereau, Stéphanie; Dehoux, Cécile; Rodriguez, Frédéric; Bodlenner, Anne; Compain, Philippe; Génisson, Yves

doi:10.1016/j.bmc.2017.02.026

Cited by 13 publications

(14 citation statements)

References 39 publications

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“…The “ all-cis ” ether 19 was obtained by Williamson synthesis following a recently reported procedure on a similar substrate [ 28 ]. Treatment of alcohol 18 with sodium hydride in dry DMF, alkylation with 1-nonyl bromide gave ether 19 with a 53% yield.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

et al. 2020

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Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors.

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Section: Resultsmentioning

confidence: 99%

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

et al. 2020

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“…The availability of LTP inhibitors remains very limited except for a few LTP types, including sterol or oxysterol transfer proteins [27][28][29][30] and CERT 13,14,17,19 . (1R, 3S)-HPA-12 and its closely related compounds have so far been the only potent inhibitors of CERT effective in living cells 13,14,17,26,31 .…”

Section: Discussionmentioning

confidence: 99%

“…(1R, 3S)-HPA-12 and its closely related compounds have so far been the only potent inhibitors of CERT effective in living cells 13,14,17,26,31 . Iminosugar-based structures were recently shown to be another type of ceramidemimicking CERT inhibitor, although their effectiveness toward living cells remains unclear 19 . In the present study, we developed (1S, 2R)-HPCB-5 as a novel potent CERT inhibitor with no apparent structural similarity to ceramides.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a potent inhibitor of CERT named (1R, 3S)-HPA-12, which contains a ceramide-like moiety, was previously developed and characterized [13][14][15][16][17] . Although several derivatives of ceramides and HPA-12 were shown to have enhanced binding affinity for the CERT START domain under cell-free conditions [18][19][20] , it is not known whether these new derivatives are capable of inhibiting CERT in living cells more potently than the original HPA-12. HPA-12 binds to the ceramidebinding pocket in the CERT START domain, thereby acting as a competitive antagonist, whereas it does not affect the ceramide-metabolizing enzymes, including ceramide synthase, SM synthase, ceramidase, and sphingomyelinase.…”

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confidence: 99%

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Natural ligand-nonmimetic inhibitors of the lipid-transfer protein CERT

et al. 2019

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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 ceramidebinding START domain, by virtual screening of~3 × 10 6 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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“…[4,5] (1R,3S)-HPA-12 binds to a ceramide-binding pocket in CERT, thereby acting as a competitive antagonist, whereas it does not affect the ceram-ide-metabolizing enzymes. [6] Nevertheless, natural ligand-mimetic compounds may directly bind not only to the desired target, but also to various undesired targets sharing the same natural ligand. Therefore, we started the development of a series of small chemicals with no apparent ceramide mimicry, but with potent inhibitory activity of the function of CERT in human cultured cells.…”

Section: Introductionmentioning

confidence: 99%

Three‐Component, One‐Pot Tandem Sonogashira/Suzuki‐Miyaura Coupling Reactions for the Synthesis of a Library of Ceramide‐Transport Protein Inhibitors Designed In Silico

et al. 2020

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We have developed a one‐pot, tandem Sonogashira/Suzuki‐Miyaura coupling reaction, which was unknown synthetically, and applied it for the synthesis of a library of potential natural ligand nonmimetic inhibitors of the lipid‐transfer protein, ceramide‐transport protein (CERT). The characteristic feature of this reaction is that the two‐step coupling reaction proceeds smoothly with only 5 mol% of palladium catalyst. Furthermore, the location of the formed carbon−carbon bond would be strictly defined because of the difference in reactivity. Therefore, many derivatives could be synthesized in high yields without the formation of regioisomeric byproducts by the same procedure. We also performed a semi‐gram scale synthesis of several derivatives to provide the bioactive assay. After synthesizing as many as 113 derivatives, we identified a non‐natural mimetic inhibitor with activity comparable to that of the known inhibitor (1R,3S)‐HPA‐12.

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Iminosugar-based ceramide mimicry for the design of new CERT START domain ligands

Cited by 13 publications

References 39 publications

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

Synthesis of “All-Cis” Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors

Natural ligand-nonmimetic inhibitors of the lipid-transfer protein CERT

Three‐Component, One‐Pot Tandem Sonogashira/Suzuki‐Miyaura Coupling Reactions for the Synthesis of a Library of Ceramide‐Transport Protein Inhibitors Designed In Silico

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