FR901459, A NOVEL IMMUNOSUPPRESSANT ISOLATED FROM Stachybotrys chartarum No. 19392

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The Journal of Antibiotics

Vol.46 , No.12(1993)pp.1788-1798

[ Full-text PDF (633K) ] [ References ]

FR901459, A NOVEL IMMUNOSUPPRESSANT ISOLATED FROM Stachybotrys

chartarum No. 19392

TAXONOMY OF THE PRODUCING ORGANISM, FERMENTATION, ISOLATION,

PHYSICO-CHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITIES

KAZUTOSHI SAKAMOTO1), EISAKU TSUJII1), MICHIYO MIYAUCHI1),

TOMOKO NAKANISHI1), MICHIO YAMASHITA1), NOBUHARU SHIGEMATSU1),

TOSHIHARU TADA2), SHIZUE IZUMI3) and MASAKUNI OKUHARA1)

1) Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.

2) Analytical Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.

3) Pharmacological Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.

[Received: 1993/07/22]

[Published: 1993/12/25]

[Released: 2006/04/19]

Abstract:

FR901459, a novel immunosuppressant, has been isolated from the

fermentation broth of Stachybotrys chartarum No. 19392. The molecular

formula of FR901459 was determined as C62H111N11O13. FR901459 was

found to be a member of the cyclosporin family. However, it is

structurally distinct from any other cyclosporins discovered so far,

in that Leu is present at position 5 instead of Val. FR901459 was

capable of prolonging the survival time of skin allografts in rats

with one third the potency of cyclosporin A.

[ Full-text PDF (633K) ] [ References ]

J Antibiot (Tokyo). 2000 May;53(5):509-15.

Related Articles, Links

The potent immunosuppressive cyclosporin FR901459 inhibits the

human P-glycoprotein and formyl peptide receptor functions.

Tiberghien F, Wenandy T, Loor F.

Immunology Laboratory, Biotechnology and Pharmacology Research

Center, Strasbourg 1 University, Illkirch, France.

By sequestering cytosolic calcineurin into a molecular complex

with cyclophilin and its consequent T-cell dysfunction, some

cyclosporins, such as CsA and FR901459 ([Thr2-Leu5-Leu10]-CsA),

display potent immunosuppressive activity. Independently on this

property, cyclosporins may display one or more other biological

activities mediated by interaction with cell surface glycoproteins.

Several cyclosporins inhibit the function of human MDRI-encoded

P-glycoprotein (Pgp), a flippase known to cause cancer multidrug

resistance, but also expressed by some normal immunocompetent cells

and by normal epithelial cells which control drug bioavailability in

vivo. CsA is known to be a potent Pgp inhibitor with a 3.2 microM IC50

in an assay where the most potent derivative SDZ PSC 833 gives a 0.49

microM IC50. FR901459 is now shown to be a good Pgp inhibitor, being

2-fold weaker only (IC50 of 6 microM) than CsA. Some cyclosporins may

also inhibit the function of the human FPR1-encoded formyl peptide

receptor (FPR), a chemotactic receptor whose absence is known to

impair antibacterial immunity. Yet this inhibition is very weak for

all, but one of them, CsH, whose 0.15 micro/M IC50 makes it a much

more potent FPR inhibitor than CsA (IC50 >10 microM in the same

assay). FR901459 is now shown to be a very potent inhibitor of FPR

function (IC50 of 0.6 microM). Since CsH shows little Pgp-inhibitory

activity and has no known immunosuppressive activity, FR901459

displays a unique pharmacological profile: like CsA, it inhibits

T-cell function; less than CsA, it can inhibit Pgp function on

selected leukocyte subsets and on epithelial barriers known to control

drug bioavailability; however, much more efficiently than CsA, it can

inhibit the FPR function, a receptor involved in some leukocytic

inflammatory responses to chemotactic peptides.

Publication Types:

* Comparative Study

* Research Support, Non-U.S. Gov't

PMID: 10908115 [PubMed - indexed for MEDLINE]