New chemotype of selective and potent inhibitors of human delta 24-dehydrocholesterol reductase

Müller, Christoph; Hemmers, Sandra; Bartl, Nicholas; Plodek, Alois; Körner, Andreas; Mirakaj, Valbona; Giera, Martin; Bracher, Franz

doi:10.1016/j.ejmech.2017.08.011

Cited by 19 publications

(40 citation statements)

References 40 publications

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“…S1 and S2, SH42 did not induce target gene expression of any of these transcription factors. As previously reported, SH42 does pose selective actions on DHCR24 within distal cholesterol biosynthesis (21). Taken together, these results provide evidence that the actions of SH42 are mediated by a desmosterol-related loop without a direct interaction with the transcription factors tested here.…”

Section: Resultssupporting

confidence: 88%

“…Using our established GC-MS assay in the scan mode (22), we also screened for other steroidal precursors of cholesterol (33) as well as oxysterols, neither of which could be detected under our experimental conditions. Additionally, we found increased blood and serum desmosterol levels under treatment with SH42, as described above and elsewhere (21). To gain further insights into molecular changes linked to SH42 treatment, we carried out comprehensive quantitative lipidomic analysis of serum and liver samples after a 3-d treatment with SH42 (without zyA) (34).…”

Section: Inhibition Of Dchr24 Leads To Increased Inflammation Resolutsupporting

confidence: 69%

“…1, the LXR target genes (23) Abca1 and Abcg1 (Srebp1c only at 5 μM) are only activated when no extracellular cholesterol is available. In turn, SH42 blocks cholesterol biosynthesis (21) and causes LXR activation via desmosterol accumulation, but not in a direct fashion; otherwise, target gene regulation would also take place when extracellular cholesterol is available. In order to further strengthen this line of argumentation, we repeated the incubation of RAW264.7 MΦ with and without FCS under cotreatment with the cholesterol-lowering drug atorvastatin, which interferes with proximal cholesterol biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

“…The chemical probe SH42 was prepared as described elsewhere (21). All animal experiments were approved by the Local Ethical Commission of the Leiden University Medical Center or the Regierungspräsidium Tübingen.…”

Section: Methodsmentioning

confidence: 99%

“…Along these lines, we reasoned that inhibition of DHCR24, leading to controlled desmosterol accumulation, is ideally suited as a master regulator of lipid metabolism, allowing initiation of an antiinflammatory and proresolving phenotype. We therefore investigated the metabolic and immunological consequences, as well as the antiinflammatory/proresolving potential, of controlled desmosterol accumulation through selective inhibition of DHCR24 using a recently published, highly in vivo active chemical probe (SH42) (half-maximal inhibitory concentration = 5 nM) (21). Initially, we evaluated the cross-reactivity of SH42 with LXRs and a set of additional transcription factors; next, we investigated the probes' effects on the course of zymosan A (zyA)-induced peritoneal inflammation.…”

Section: Significancementioning

confidence: 99%

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Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution

Körner

Zhou

Müller

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Targeting metabolism through bioactive key metabolites is an upcoming future therapeutic strategy. We questioned how modifying intracellular lipid metabolism could be a possible means for alleviating inflammation. Using a recently developed chemical probe (SH42), we inhibited distal cholesterol biosynthesis through selective inhibition of Δ24-dehydrocholesterol reductase (DHCR24). Inhibition of DHCR24 led to an antiinflammatory/proresolving phenotype in a murine peritonitis model. Subsequently, we investigated several omics layers in order to link our phenotypic observations with key metabolic alterations. Lipidomic analysis revealed a significant increase in endogenous polyunsaturated fatty acid (PUFA) biosynthesis. These data integrated with gene expression analysis, revealing increased expression of the desaturase Fads6 and the key proresolving enzyme Alox-12/15. Protein array analysis, as well as immune cell phenotype and functional analysis, substantiated these results confirming the antiinflammatory/proresolving phenotype. Ultimately, lipid mediator (LM) analysis revealed the increased production of bioactive lipids, channeling the observed metabolic alterations into a key class of metabolites known for their capacity to change the inflammatory phenotype.

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Section: Resultssupporting

confidence: 88%

Section: Inhibition Of Dchr24 Leads To Increased Inflammation Resolutsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution

Körner

Zhou

Müller

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Synthesis of Seco‐Analogues of the DHCR24 Inhibitor SH‐42

et al. 2020

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In a project aimed at the further development of the potent steroidal anti‐inflammatory Δ24‐dehydrocholesterol reductase (DHCR24) inhibitor SH‐42 we worked out routes to ring B seco‐steroidal analogues. The required building blocks, bearing rings C and D of the parent steroidal structure, were synthesised starting from ergocalciferol. The novel seco‐analogues carry aromatic residues as ring A equivalents at C‐4 position with variation of the linker length resulting in 4‐aryl‐, 4‐benzyl‐ and 4‐(arylethyl)perhydroindanes. As saturated analogues of the latter 4‐(cyclohexylethyl)perhydroindanes were prepared. Moreover, aromatic and aliphatic residues were attached to C‐5 position of the perhydroindane scaffold. Unfortunately, none of these structurally diverse seco‐analogues of SH‐42 showed noteworthy inhibition of target enzyme DHCR24, indicating the relevance of the intact steroidal structure for the development of potent inhibitors of this enzyme.

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