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/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.
Ondeykal
John G
JG
Merck Research Laboratories, Rahway, NJ, USA. john_ondeyka@merck.com
Herath
Kithsiri B
KB
Jayasuriya
Hiranthi
H
Polishook
Jon D
JD
Bills
Gerald F
GF
Dombrowski
Anne W
AW
Mojena
Marina
M
Koch
Gregory
G
DiSalvo
Jerry
J
DeMartino
Julie
J
Guan
Ziqiang
Z
Nanakorn
Weerachai
W
Morenberg
Cori M
CM
Balick
Michael J
MJ
Stevenson
Dennis W
DW
Slattery
Marc
M
Borris
Robert P
RP
Singh
Sheo B
SB
D000818:Animals; D001430:Bacteriocins; D001685:Biological Factors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D005227:Fatty Acids / Q000302:isolation & purification / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000302:isolation & purification / Q000494:pharmacology; D051381:Rats; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
D001430:Bacteriocins; D001685:Biological Factors; C515189:Cxcr3 protein, rat; D005227:Fatty Acids; D010455:Peptides; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; C040522:duramycin; C019357:dioscin; D004144:Diosgenin