Identification of plant-derived natural products as potential inhibitors of the Mycobacterium tuberculosis proteasome

BMC Complementary and Alternative Medicine
Yuejuan ZhengHuiyong Zhang

Abstract

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. 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 μM) were detected by this method using MG132 as a positive control. 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. These data indicate that flavonoids represent a basis for rational structural design in the process of novel anti-tuberculosis drug discovery.

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Related Concepts

Proteasome Pathway
Bacterial Proteins
Bioflavonoids
Tuberculosis
Natural Products
3-hydroxyflavone
Oligopeptides
Fluorescent stain
Flavonoids
Leupeptins

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