Isolation and structures of novel fungal metabolites as chemokine receptor (CCR2) antagonists.
The chemokine receptor, CCR2, is predominantly expressed on monocytes/macrophages, and on a subset of memory T cells. It binds to several CC type chemokines of the monocyte chemoattractant protein (MCP) family of which MCP-1 exhibits the highest affinity. CCR2/MCP-1 expression/association in monocyte/macrophage/T cells has been associated with inflammatory processes such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. Neutralization of CCR2 with either a peptide or receptor antagonist results in the prevention of joint swelling in rodent models of arthritis. In this paper, bioassay-guided discovery of CCR2 receptor antagonists derived from natural product extracts are reported. These antagonists belong to two main classes exemplified by bisthiodiketopiperazines and cytochalasins. Six compounds, including emestrin, two new emestrin analogs, and chaetomin represent the first group of compounds. These compounds inhibited the binding of MCP-1 to CCR2 (CHO membrane) with IC50 values of 0.8 to 9 microM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC50's ranging from 4-9 microM. Cytochalasins A and B represented the second group and inhibited the binding activity with IC50 values of 5 and 188 microM, respectively. This is the first report of natural product antagonists of the CCR2 receptor.
Herath
Kithsiri B
KB
Merck Research Laboratories, Rahway, NJ 07065, USA.
Jayasuriya
Hiranthi
H
Ondeyka
John G
JG
Polishook
Jon D
JD
Bills
Gerald F
GF
Dombrowski
Anne W
AW
Cabello
Angeles
A
Vicario
Pasquale P
PP
Zweerink
Hans
H
Guan
Ziqiang
Z
Singh
Sheo B
SB
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003572:Cytochalasins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005658:Fungi / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D003572:Cytochalasins; D004220:Disulfides; D026121:Indole Alkaloids; D010446:Peptide Fragments; D010879:Piperazines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C106929:monocyte chemoattractant protein 1 (9-76); C001598:chetomin; C067458:emestrin