TY - JOUR
AU1 - Herath, Kithsiri B
AU2 - Jayasuriya, Hiranthi
AU3 - Ondeyka, John G
AU4 - Polishook, Jon D
AU5 - Bills, Gerald F
AU6 - Dombrowski, Anne W
AU7 - Cabello, Angeles
AU8 - Vicario, Pasquale P
AU9 - Zweerink, Hans
AU1 - Guan, Ziqiang
AU1 - Singh, Sheo B
AB - 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 bis-thiodiketopiperazines 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 µM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC50′S ranging from 4∼9 µM. Cytochalasins A and B represented the second group and inhibited the binding activity with IC50 values of 5 and 188 µM, respectively. This is the first report of natural product antagonists of the CCR2 receptor.
TI - Isolation and Structures of Novel Fungal Metabolites as Chemokine Receptor (CCR2) Antagonists
JF - The Journal of Antibiotics
DO - 10.1038/ja.2005.94
DA - 2005-11-01
UR - https://www.deepdyve.com/lp/springer-journals/isolation-and-structures-of-novel-fungal-metabolites-as-chemokine-kfX9If44oH
SP - 686
EP - 694
VL - 58
IS - 11
DP - DeepDyve
ER -