Pentacyclic triterpenoids
are considered to be the potential HMGB1
inhibitors, but due to the limited number of hydrogen bond donors
and the number of rotatable bonds in the rigid skeletons, their further
chemical biology research with this target was restricted. To improve
these profiles, microbial-catalyzed Baeyer–Villiger oxidation
of the primary ursane and oleanane-type triterpenoids including uvaol
(
1
), erythrodiol (
2
), oleanolic acid (
3
), and ursolic acid (
4
) was performed by
Streptomyces olivaceus
CICC 23628. As a result, ten
new and one known A-ring cleaved metabolites were obtained and the
possible biogenetic pathways were also discussed based on the HPLC-MS
analysis. Furthermore, the direct interactions between compounds
1d
,
2b
, and HMGB1 were observed by the biolayer
interferometry technique. Molecular docking revealed that the newly
introduced vicinal diol at C-4, C-24, and the hydroxyl group at C-21
of compound
1d
are crucial for binding with HMGB1. The
cellular assay showed that co-treatment of
1d
could
significantly block HMGB1-activated nitric oxide release with an IC
50
value of 9.37 μM on RAW 264.7 cells. Altogether, our
research provides some insights into 3,4-
seco
-triterpenes
as potential anti-inflammatory candidates for the discovery of novel
HMGB1 inhibitors.
Background
High mobility group box 1 protein (HMGB1), a lethal late inflammatory mediator, contributes to the pathogenesis of diverse inflammatory and infectious diseases. Astragaloside IV and calycosin as active ingredients in Astragalus membranaceus, possess potent regulatory ability on HMGB1-induced inflammation, however, the interaction between these two phytochemicals and HMGB1 has not been elucidated yet.
Methods
To further investigate the interaction of astragaloside IV, calycosin with HMGB1 protein, surface plasma resonance (SPR) and a series of spectroscopic methods, including UV spectra, fluorescence spectroscopy, circular dichroism (CD), were used. Molecular docking was also carried out to predict the atomic level’s binding modes between two components and HMGB1.
Results
Astragaloside IV and calycosin were found to be able to bind HMGB1 directly and affect the secondary structure and environment of the chromogenic amino acids of HMGB1 to different extents. In silico, astragaloside IV and calycosin showed a synergistic effect by binding to the two independent domains B-box and A-box in HMGB1, respectively, where hydrogen and hydrophobicity bonds were regarded as the crucial forces.
Conclusion
These findings showed that the interaction of astragaloside IV and calycosin with HMGB1 impaired its proinflammatory cytokines function, providing a new perspective for understanding the mechanism of A. membranaceus in treating aseptic and infectious diseases.
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