Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor

Swamy, Mahadeva M. M.; Murai, Yuta; Ohno, Yusuke; Jojima, Keisuke; Kihara, Akio; Mitsutake, Susumu; Igarashi, Yasuyuki; Yu, Jian; Yao, Ming; Suga, Yoshiko; Anetai, Masaki; Monde, Kenji

doi:10.1039/c8cc05595e

Cited by 9 publications

(8 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These effects could be explained by the modulation of S1Pdependent signals through formation of S1P receptor heterodimers (Van Brocklyn et al, 2002;Zaslavsky et al, 2006;Siehler and Manning, 2002;Kluk and Hla, 2002), which has been previously described in other cells and also for other receptors expressed in granulosa cells (Casarini et al, 2018a). However, we can not exclude that synthetic ligands and S1P may activate different conformational states of the receptors, and hence a distinct profile of intracellular signaling cascades (Troupiotis-Tsaïlaki et al, 2017;Swamy et al, 2018;Jiang and Zhang, 2019).…”

Section: Discussionmentioning

confidence: 81%

Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells

Paradiso

Lazzaretti

Sperduti

et al. 2021

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

Background and aims: Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At nanomolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P 1-5 , modulating different signaling pathways. S1P 1 and S1P 3 are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PRstimulation in this context. METHODS AND RESULTS. hGLC and hGL5 cells were treated with a fixed dose (0.1 μM) of S1P, or by S1P 1 -and S1P 3 -specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1Pdependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca 2+ channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P 2 or S1P 3 with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulinencoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions. Conclusions: This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P-S1PR axis may cooperate with gonadotropins in modulating follicle development.

show abstract

Section: Discussionmentioning

confidence: 81%

Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells

Paradiso

Lazzaretti

Sperduti

et al. 2021

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

show abstract

“…The ability of DCA and its derivatives to inhibit the SMS isozymes SMS1 and SMS2 was evaluated using a cell lysate assay and the fluorescent substrate C6-NBD (4-nitrobenzo-2-oxa-1,3-diazole)-Cer. DCA ( 1 ) and compounds 4 , 6 , and 7 showed relatively moderate inhibitory activities, with IC 50 values of 7, 17, 9, and 4 μM, respectively, for SMS1, and 4, 10, 7, and 5 μM, respectively, for SMS2 ( Figure 1 ), similar to other natural compounds [ 13 , 14 ]. These findings indicated that the methyl esters of DCA derivatives, compounds 2 , 3 , and 5 , were inactive in these assays.…”

Section: Resultsmentioning

confidence: 57%

“…However, the SMS has not been succeeded in its crystallization. Therefore, a direct comparison with the previously isolated SMS inhibitor ginkgolic acid [ 13 ] has been examined. The chemical similarity of ginkogolic acid to DCA, as it is a long alkyl chain and a carboxylic acid moiety in an aromatic ring, shows that these two inhibitors also have the same functional group participation to inhibit SMS.…”

Section: Resultsmentioning

confidence: 99%

“…SMS knockout mice showed a decrease in plasma concentrations of inflammatory cytokines [ 8 ], as well as resistance to the development of high-fat diet-induced obesity [ 9 ], insulin resistance [ 10 ], Alzheimer’s disease [ 11 ], and tumorigenesis [ 12 ]. SMS activity was shown to be inhibited by the naturally occurring compounds ginkgolic acid, from the leaves of Gingko biloba [ 13 ], and malabaricones A–C and E, from the fruits of M. cinnamomea [ 14 ]. The latter inhibitors may be especially safe, with fewer side effects than other SMS inhibitors, because they were isolated from an edible fruit.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Daurichromenic Acid from the Chinese Traditional Medicinal Plant Rhododendron dauricum Inhibits Sphingomyelin Synthase and Aβ Aggregation

et al. 2020

Self Cite

View full text Add to dashboard Cite

Species of the genus Rhododendron have been used in traditional Chinese medicine, with the medicinal herb “Manshanfong” used as an expectorant and for the treatment of acute bronchitis. Daurichromenic acid (DCA), a constituent of Rhododendron dauricum, is a meroterpenoid with antibacterial, anti-HIV, and anti-inflammatory activities. However, the mechanisms underlying these pharmacologic activities are poorly understood. To develop new drugs based on DCA, more information is required regarding its interactions with biomolecules. The present study showed that DCA inhibits the activity of the enzyme sphingomyelin synthase, with an IC50 of 4 µM. The structure–activity relationships between DCA and sphingomyelin synthase were evaluated using derivatives and cyclized hongoquercin A. In addition, DCA was found to inhibit amyloid β aggregation. These results may help in the design of effective drugs based on DCA.

show abstract

“…This assay uses a fluorescent (D)‐ erythro C6‐NBD (4‐nitrobenzo‐2‐oxa‐1,3‐diazole)‐Cer analog as a substrate into SM moiety. As shown in Table , several ceramides showed relatively moderate inhibitory activities (IC 50 0.2‐1 μM; Table ) compared with those of our previously reported natural compounds . Furthermore, to determine the differences in the inhibitory activities of the four stereoisomers, we represented the IC 50 values as a heatmap graphical representation in which individual values contained in a matrix are displayed as colors.…”

Section: Resultsmentioning

confidence: 99%

Chiral combinatorial preparation and biological evaluation of unique ceramides for inhibition of sphingomyelin synthase

et al. 2020

Self Cite

View full text Add to dashboard Cite

Enantiomers or diastereomers of chiral bioactive compounds often exhibit different biological and toxicological properties. Here, we report the efficient synthesis of four stereoisomers of sphingosine and derivatization of unique chiral ceramides through a combinatorial chemistry by solid‐phase activated resin ester. In addition, to test the effectivity of stereochemistry of ceramide, we demonstrated a cell‐based assay of sphingomyelin synthase inhibition in the presence ofchiral unique ceramides, which suggested that libraries of this sort will be a rich source of biologically active synthetic molecules.

show abstract

Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor

Abstract: A monophosphate derivative of ginkgolic acid binds to sphingosine 1-phosphate (S1P) receptors to perform similar functions to the lipid mediator S1P.

Cited by 9 publications

References 30 publications

Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells

Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells

Daurichromenic Acid from the Chinese Traditional Medicinal Plant Rhododendron dauricum Inhibits Sphingomyelin Synthase and Aβ Aggregation

Chiral combinatorial preparation and biological evaluation of unique ceramides for inhibition of sphingomyelin synthase

Contact Info

Product

Resources

About