Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3 |
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Authors: | John G. Ondeyka Kithsiri b. Herath Hiranthi Jayasuriya Jon D. Polishook Gerald F. Bills Anne W. Dombrowski Marina Mojena Gregory Koch Jerry DiSalvo Julie DeMartino Ziqiang Guan Weerachai Nanakorn Cori M. Morenberg Michael J. Balick Dennis W. Stevenson Marc Slattery Robert P. Borris Sheo B. Singh |
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Affiliation: | (1) Merck Research Laboratories, Rahway, NJ, USA;(2) CIBE, Merck Sharp & Dohme de Espana, S. A. Josefa Valcárcel, Madrid, Spain;(3) The Forest Herbarium, Royal Forest Department, Bangkok, Thailand;(4) Institute of Economic Botany, The New York Botanical Garden, Bronx, NY, USA;(5) Nationa Center for Natural Products Research, Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, MS, USA |
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Abstract: | 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 M) 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 125 I IP-10/CXCR3 binding assay. Duramycin was the most potent with an IC50 of 0.1 M. Roselipins 2A, 2B and 1A showed IC50 values of 14.6, 23.5, and 41 M, respectively. Diosgenin glycosides dioscin, hypoglaucin A and kallstroemin D exhibited IC50 values of 2.1, 0.47 and 3 M, respectively. A novel cyclic 3-alkyl pyridinium salt isolated from a sponge displayed a binding IC50 of 0.67 M. |
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Keywords: | chemokines CXCL10 CXCR3 receptor natural products extract libraries transplantation |
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