Evaluation of Anti-Proprotein Convertase Activity of Diterpene Andrographolid Derived Products


SEA, a mixture of succinoyl ester derivatives of andrographolid, previously shown to be the first in vitro nonpeptide inhibitor of Proprotein Convertases (PC) PC1, furin, and PC7 [Basak, et al., Biochem. J. 1999; 338: 107–113] has been tested ex vivo for its anti-Proprotein Convertase (PC) activity. SEA blocks PC-mediated cleavages of proBDNF (Brain Derived Neurotrophic Factor) (RVRR128↓HS) and surface envelope glycoprotein gp160 of HIV (RERR511↓AV) in a dose dependent manner. 25 μM of SEA completely blocks the cleavage of 32 kDa proBDNF into its 14 kDa mature form while 75 μM prevents significantly HIV gp160 processing into gp41. The estimated IC50 value for the latter is ∼ 40 μM. At higher concentration, SEA is partly cytotoxic to the cells, with less protein secretion in culture medium. In an effort to examine further, the anti-PC activity of SEA and other andrographolid products, we examined their effects on human leukemic cell growth. Data showed a 15–50% decrease in growth in presence of SEA depending on the concentration used. These findings may provide a rationale for designing nonpeptide inhibitors of PCs based on androgholide molecule present in abundance in the medicinally active plant Andrographis paniculata (AP)