Background: The Mycobacterium tuberculosis (Mtb) proteasome has been established as a viable target for the development of anti-tuberculosis agents. In this study, the inhibitory activities of 100 plant-derived natural products on the Mtb proteasome were analyzed to identify novel potential inhibitors.
Methods: The fluorescent substrate Suc-Leu-Leu-Val-Tyr-AMC can be hydrolyzed by the proteasome to release free AMC, the fluorescence of which is proportional to the proteasome activity. The inhibitory activities of 100 natural products (each at a final concentration of 200 mu M) were detected by this method using MG132 as a positive control.
Results: Twelve of these natural products (10 of which were flavonoids) inhibited the activity of the Mtb proteasome by more than 65%. Comparison of the structural differences between the flavonoids with good inhibitory activity and those without inhibitory activity revealed that the hydroxyl at the flavonoid C ring C-3 or the hydroxyl/methoxyl at the flavonoid A ring C-6 were critical for the inhibition of proteasomal activity.
Conclusions: These data indicate that flavonoids represent a basis for rational structural design in the process of novel anti-tuberculosis drug discovery.
[1]Shanghai Univ Tradit Chinese Med, Dept Microbiol & Immunol, Shanghai 201203, Peoples R China.
[2]Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Shanghai 200080, Peoples R China.
[3]Shanghai Univ Tradit Chinese Med, Longhua Hosp, Shanghai 200032, Peoples R China.
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