Inhibition of the human chemokine receptor CCR5 by variecolin and variecolol and isolation of four new variecolin analogues, emericolins A-D, from Emericella aurantiobrunnea.
An extract from the fungus Emericella aurantiobrunnea was found to compete with macrophage inflammatory protein (MIP)-1alpha for binding to human CCR5 in a scintillation proximity assay (SPA). Bioassay-guided fractionation led to the isolation of variecolin (1) and variecolol (2), which had IC50 values of 9 and 32 microM, respectively. An X-ray crystal structure of variecolin (1) was obtained for the first time. Also isolated were four new inactive analogues, emericolin A (3), B (4), C (5), and D (6), and the relative stereochemistry of these compounds was determined by NMR methods using ROESY spectra and 1H/1H coupling constants.
Yoganathan
K
K
MerLion Pharmaceuticals, 1 Science Park Road, The Capricorn #05-01, Singapore Science Park II, 117528.
Rossant
Christine
C
Glover
Robert P
RP
Cao
Shugeng
S
Vittal
Jagadese J
JJ
Ng
Siewbee
S
Huang
Yicun
Y
Buss
Antony D
AD
Butler
Mark S
MS
D001203:Ascomycota / Q000737:chemistry*; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D013729:Terpenes; C433945:variecolin; C493694:variecolol