A Mechanism-Based Sphingosine-1-phosphate Lyase Inhibitor

Pons, Guillem; Riba, Daniel; Casasampere, Mireia; Izquierdo, E.; Abad, José Luı́s; Fabriás, Gemma; Ortega, Pilar Gema Rodríguez; González, Juan Jesús López; Montejo, Manuel; Casas, Josefina; Delgado, Antonio

doi:10.1021/acs.joc.9b02420

Cited by 6 publications

(2 citation statements)

References 39 publications

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“…At the same time, SPL inhibition augments tissue levels of the trophic muscle factor S1P, leading to an expansion of the SC population, thereby potentially improving the regenerative capacity of dystrophic muscle. Multiple SPL inhibitors have been generated to date [ 41 , 42 ]. LX2931 has the advantage of having been tested in human clinical trials [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

Garza-Rodea

Moore

Zamora-Pineda

et al. 2022

IJMS

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Duchenne muscular dystrophy (DMD) is a congenital myopathy caused by mutations in the dystrophin gene. DMD pathology is marked by myositis, muscle fiber degeneration, and eventual muscle replacement by fibrosis and adipose tissue. Satellite cells (SC) are muscle stem cells critical for muscle regeneration. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes SC proliferation, regulates lymphocyte trafficking, and is irreversibly degraded by sphingosine phosphate lyase (SPL). Here, we show that SPL is virtually absent in normal human and murine skeletal muscle but highly expressed in inflammatory infiltrates and degenerating fibers of dystrophic DMD muscle. In mdx mice that model DMD, high SPL expression is correlated with dysregulated S1P metabolism. Perinatal delivery of the SPL inhibitor LX2931 to mdx mice augmented muscle S1P and SC numbers, reduced leukocytes in peripheral blood and skeletal muscle, and attenuated muscle inflammation and degeneration. The effect on SC was also observed in SCID/mdx mice that lack mature T and B lymphocytes. Transcriptional profiling in the skeletal muscles of LX2931-treated vs. control mdx mice demonstrated changes in innate and adaptive immune functions, plasma membrane interactions with the extracellular matrix (ECM), and axon guidance, a known function of SC. Our cumulative findings suggest that by raising muscle S1P and simultaneously disrupting the chemotactic gradient required for lymphocyte egress, SPL inhibition exerts a combination of muscle-intrinsic and systemic effects that are beneficial in the context of muscular dystrophy.

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Section: Discussionmentioning

confidence: 99%

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

Garza-Rodea

Moore

Zamora-Pineda

et al. 2022

IJMS

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“…3,4 However, the reaction outcomes are often limited with respect to the achieved diastereoselectivities and occasionally require additional oxidation/reduction sequences to increase the overall yield of the desired diastereomer. [5][6][7] Furthermore, N-Boc protection most often results in the formation of rotameric mixtures, which render proper NMR analysis challenging. 8 Although the use of the sterically more hindered benzyl protecting group results in high diastereoselectivities, their removal requires reductive deprotection conditions, which are incompatible with unsaturated functionalities.…”

mentioning

confidence: 99%

Application of pyrrolo-protected amino aldehydes in the stereoselective synthesis of anti-1,2-amino alcohols

Sauer

Beemelmanns

2022

Chem. Commun.

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Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Blaho

2020

Druggable Lipid Signaling Pathways

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Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.

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A Mechanism-Based Sphingosine-1-phosphate Lyase Inhibitor

Cited by 6 publications

References 39 publications

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

Application of pyrrolo-protected amino aldehydes in the stereoselective synthesis of anti-1,2-amino alcohols

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

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