Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters

Abstract

Studies were performed to investigate the prohormone/proprotein convertase (PC)-inhibitory properties of chemical constituents of the medicinally active plant Andrographis paniculata (AP; from the family Acanthaceae), also known as 'King of Bitters'. Among the individual components tested against the clinically important convertases, furin and PC1, neoandrographolide (a C3 O-glucoside derivative of the major constituent andrographolide) exhibited the highest inhibitory action with an IC50 of 53.5 microM against furin. The data further revealed that although andrographolide, the major bitter principle of AP, exhibited a relatively small enzyme inhibition (IC50=1.0 mM and Ki=200 microM against furin), upon succinoylation, its inhibitory action against the above convertases was enhanced significantly with a Ki in the low micromolar range (<30 microM), suggesting that a specific structural modification of the andrographolide skeleton may be exploited to develop a new class of non-peptide inhibitors of PCs. When tested against PC7, these succinoylated derivatives of andrographolide also displayed strong inhibitory action, with Ki values again in the low micromolar range. This potentially interesting observation may be attributed to the reported anti-HIV property of 14-dehydroandrographolide succinic acid monoester (DASM). It is suggested here that DASM, by virtue of this protease inhibitory property, possibly acts by suppressing the proteolytic cleavage of envelope glycoprotein gp160 of HIV, which is known to be PC-mediated, particularly by furin and PC7.

Andrographolide: A New Plant‐Derived Antineoplastic Entity on Horizon

“…These compounds have the potential to be developed as antitumor agents. These results are supported by a different finding, where it was demonstrated that the succinoyl ester of andrographolide significantly inhibited proprotein convertases and thus displayed potent antiviral activities against HIV-1 and HIV-2 [89]. These results emphasize that some of the derivatives of andrographolide might be much more potent that the parent compound itself and call for a dedicated line of investigations to prove their potential.…”

On the cutting edge of proprotein convertase pharmacology: from molecular concepts to clinical applications

“…Some groups have previously investigated the inhibitory effects of some molecules that could be used as lead compounds for the molecular scaffolds that are required for further inhibitor development. A number of natural compounds derived from plants called andrographolides have shown weak potency inhibition (low micromolar inhibition) against furin, PC1/3 and PC7 (105). All of the effective constituents of the plant Andrographis paniculata have a diterpine labdane skeleton in common, shown in Table 2, that could be exploited to generate inhibitors as good as peptide-based compounds.…”

Mediation of Endogenous β‐Endorphin in the Plasma Glucose‐Lowering Action of Herbal Products Observed in Type 1‐Like Diabetic Rats

“…In addition, andrographolide belongs to the diterpene lactones, and has been reported to have multiple pharmacologic properties, such as protozoacidal activity, inhibition of platelet aggregation, inhibition of protein convertases-1 and -7, and furin, stimulation of cell differentiation, and anti-hepatotoxic activity, and may be developed as the drug for treatment of tissue injury, septic shock, and autoimmune diseases [110–115]. We found that puerarin [90–92] and andrographolide [93–95] also posses the ability to activate α 1 -ARs, especially the α 1A -subtype, to enhance β -endorphin secretion from adrenal glands of STZ-diabetic rats (Table 1, Figure 1).…”