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Lipidomics Gateway (27 October 2010) [doi:10.1038/lipidmaps.2010.34]

The fungal metabolite from which fingolimod — a pioneering oral disease-modifying multiple sclerosis drug — was derived.

The structure of 2-Amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxoicos-6-enoic acid. Visit myriocin in the LIPID MAPS structure database for more molecular information.

Myriocin, systematic name 2-Amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxoicos-6-enoic acid, is a metabolite of the fungus Isaria sinclairii and a sphingoid base analog with immunosuppressive properties. Its chemical derivative fingolimod, systematic name 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, was approved on 22 September 2010 by the US Food and Drug Administration for the treatment of multiple sclerosis (MS) — a chronic autoimmune disease that affects millions of people worldwide. It is the first orally administered disease-modifying treatment for MS to be approved in the United States and uses a unique strategy to disrupt the disease's attack on the central nervous system (CNS).

One clue that Isaria sinclairii might yield a useful drug came from traditional Chinese medicine — it has been used for centuries as an “elixir for eternal youth”. Another clue was Isaria sinclairii's ability to attack other organisms — in this case, insects — with a chemical arsenal. In 1994, a team of Japanese scientists was the first to extract and observe the immunosuppressive effects of myriocin 1 . Soon after this, a program of derivatization to improve effectiveness and reduce toxicity resulted in FTY720, or fingolimod 2 .

Fifteen years later, extensive research exploring the therapeutic potential of fingolimod has now led to its US regulatory approval for the treatment of relapsing forms of MS 3 . During this period, the key to fingolimod's mode of action was uncovered — modulation of the cell-surface receptors for sphingosine-1-phosphate (S1P) 4 . Because of its structural similarity to sphingosine, fingolimod can also be phosphorylated at its aminodiol head group by sphingosine kinases 5 . Phosphoro-fingolimod acts as a functional antagonist of S1P1 receptors, internalizing them. It is thought that this leads to the retention of certain immune cells in the lymph nodes, thereby preventing them from migration into the CNS and involvement in the autoimmune attacks characteristic of MS 3 .

Immune system modulation is not myriocin's only useful contribution to biochemistry — it can also deplete sphingolipids from cells, because it inhibits the enzyme serine palmitoyltransferase7 which catalyses the formation of sphingosine, a precursor of sphingolipids.

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- Copyright © 2010 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission


  1. Fujuta, T. et al. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite.

    J Antibiot (Tokyo) 47, 208-215 (1994).

  2. Fujuta, T. et al. Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyriocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives.

    J Antibiot (Tokyo) 47, 216-224 (1994).

  3. Brinkmann, V. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis.

    Nat. Rev. Drug Discov. (2010). doi:10.1038/nrd3248

  4. Brinkmann, V. Sphingosine-1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology.

    Pharmacol. Ther. 115, 84-105 (2007). doi:10.1016/j.pharmthera.2007.04.006

  5. Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine-1-phosphate receptors.

    J. Biol. Chem. 277, 21453-21457 (2002). doi:10.1074/jbc.C200176200

  6. Chen, J.K. et al. The identification of myriocin-binding proteins.

    Chem. Biol. 6, 221-235 (1999). doi:10.1016/S1074-5521(99)80038-6

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