Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3

The chemokines (CXCL9, CXCL10 and CXCL11) and associated CXCR3 receptor are expressed during the inflammatory process from multiple sclerosis, atherosclerosis or organ transplantation resulting in the recruitment of lymphocytes leading to tissue damage. It is hypothesized that blocking of the ligand...

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Bibliographic Details
Published in:Molecular diversity 2005, Vol.9 (1-3), p.123-129
Main Authors: Ondeykal, John G, Herath, Kithsiri B, Jayasuriya, Hiranthi, Polishook, Jon D, Bills, Gerald F, Dombrowski, Anne W, Mojena, Marina, Koch, Gregory, DiSalvo, Jerry, DeMartino, Julie, Guan, Ziqiang, Nanakorn, Weerachai, Morenberg, Cori M, Balick, Michael J, Stevenson, Dennis W, Slattery, Marc, Borris, Robert P, Singh, Sheo B
Format: Article
Language:English
Subjects:
Actinomycetes
Animals
Bacteriocins
Biological Factors - pharmacology
Cell Line, Tumor
Diosgenin - analogs & derivatives
Diosgenin - isolation & purification
Diosgenin - pharmacology
Fatty Acids - isolation & purification
Fatty Acids - pharmacology
Models, Molecular
Molecular Conformation
Natural products
Peptides - isolation & purification
Peptides - pharmacology
Rats
Receptors, Chemokine - antagonists & inhibitors
Receptors, CXCR3
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Summary:The chemokines (CXCL9, CXCL10 and CXCL11) and associated CXCR3 receptor are expressed during the inflammatory process from multiple sclerosis, atherosclerosis or organ transplantation resulting in the recruitment of lymphocytes leading to tissue damage. It is hypothesized that blocking of the ligand/CXCR3 receptor interaction has potential to provide opportunity for development of agents that would block tissue rejection. In this paper, four classes of natural product inhibitors (IC50 ranging 0.1-41 microM) have been described that block the CXCR3 receptor interaction of IP-10 ligand. These include a cyclic thiopeptide (duramycin), polyketide glycosides (roselipins), steroidal glycosides (hypoglausin A and dioscin) and a novel alkyl pyridinium alkaloid that were isolated by bioassay-guided fractionation of the organic extracts derived from actinomycete, fungal, plant and marine sources and discovered using 125I IP-10/CXCR3 binding assay. Duramycin was the most potent with an IC50 of 0.1 microM. Roselipins 2A, 2B and 1A showed IC50 values of 14.6, 23.5, and 41 microM, respectively. Diosgenin glycosides dioscin, hypoglaucin A and kallstroemin D exhibited IC50 values of 2.1, 0.47 and 3 microM, respectively. A novel cyclic 3-alkyl pyridinium salt isolated from a sponge displayed a binding IC50 of 0.67 microM.
ISSN:1381-1991
1573-501X
DOI:10.1007/s11030-005-1296-8