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 µM 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 µM against furin), upon succinoylation, its inhibitory action against the above convertases was enhanced significantly with a Ki in the low micromolar range (< 30 µM), 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.
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February 1999
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Research Article| February 08 1999
Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters
Ajoy BASAK;
*Laboratories of Structure and Metabolism of Neuropeptides, Clinical Research Institute of Montréal (Affiliated to the University of Montréal), 110 Pine Avenue West, Montréal, Qué H2W 1R7, Canada
2To whom correspondence should be addressed (e-mail Basaka@ircm.umontreal.ca).
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Sam COOPER;
Sam COOPER
†INRS-Santé, 245 boul. Hymus, Pointe Claire, Qué H9R 1G6, Canada
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Andreé G. ROBERGE;
Andreé G. ROBERGE
†INRS-Santé, 245 boul. Hymus, Pointe Claire, Qué H9R 1G6, Canada
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Upen K. BANIK;
Upen K. BANIK
‡Bioscan Continental Inc, Ste-Eustache, Qué J7R 5R4, Canada
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Michel CHRÉTIEN;
Michel CHRÉTIEN 1
§Molecular Neuroendocrinology, Clinical Research Institute of Montréal (Affiliated to the University of Montréal), 110 Pine Avenue West, Montréal, Qué H2W 1R7, Canada
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Nabil G. SEIDAH
Nabil G. SEIDAH
║Biochemical Neuroendocrinology, Clinical Research Institute of Montréal (Affiliated to the University of Montréal), 110 Pine Avenue West, Montréal, Qué H2W 1R7, Canada
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Publisher: Portland Press Ltd
Received: June 24 1998
Revision Received: October 28 1998
Accepted: November 24 1998
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1999
1999
Biochem J (1999) 338 (1): 107–113.
Article history
Received:
June 24 1998
Revision Received:
October 28 1998
Accepted:
November 24 1998
Citation
Ajoy BASAK, Sam COOPER, Andreé G. ROBERGE, Upen K. BANIK, Michel CHRÉTIEN, Nabil G. SEIDAH; Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters. Biochem J 15 February 1999; 338 (1): 107–113. doi: https://doi.org/10.1042/bj3380107
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