Cyclo(dehydrohistidyl-L-tryptophyl) inhibits nitric oxide production by preventing the dimerization of inducible nitric oxide synthase

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Title
Cyclo(dehydrohistidyl-L-tryptophyl) inhibits nitric oxide production by preventing the dimerization of inducible nitric oxide synthase
Author(s)
Mi Jin Sohn; G M Hur; H S Byun; Won Gon Kim
Bibliographic Citation
Biochemical Pharmacology, vol. 75, no. 4, pp. 923-930
Publication Year
2008
Abstract
Dimerization of inducible NOS has been known to be a potential therapeutic target for iNOS-mediated pathologies. Cyclic dipeptides are among the simplest peptides commonly found as by-products of food processing or metabolites of microorganisms. In this study, we found that cyclo(dehydrohistidyl-l-tryptophyl) (CDHT), a cyclic dipeptide from an unidentified fungal strain Fb956, prevents iNOS dimerization in activated microglial BV-2 cells. CDHT inhibited NO production with an IC50 of 6.5 μM in LPS-treated BV-2 cells. Western blot analysis and iNOS activity measurement of fractions from size-exclusion chromatography of cell lysates indicated that CDHT inhibits dimerization of iNOS, while it has no effect on iNOS expression or enzyme activity. The CDHT inhibition of iNOS dimerization was confirmed by partially denaturing SDS-PAGE analysis. In contrast, CDHT did not affect cGMP production in endothelial HUVEC cells, which indicates no inhibition of endothelial NOS activity. These results reveal that CDHT, one of the simplest and cyclic dipeptides, selectively inhibits NO production by inhibiting iNOS dimerization, and could be a useful therapeutic agent for inflammation-mediated diseases.
Keyword
BV-2 microgliaCyclo(dehydrohistidyl-l-tryptophyl)DimerizationiNOSLPSNitric oxide
ISSN
0006-2952
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bcp.2007.10.021
Type
Article
Appears in Collections:
Division of Research on National Challenges > Infectious Disease Research Center > 1. Journal Articles
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