Inhibition of Serine Proteases by Anti-Inflammatory Triterpenoids

Abstract

The lupane triterpenoid lupeol, the ursane triterpenoid α-amyrin and esters of these compounds are present in the bark of roots of Alstonia boonei (Apocynaceae) and have anti-inflammatory properties. α-Amyrin is a competitive inhibitor of bovine trypsin and chymotrypsin (K_i values 29 μM and 18 μM, respectively). Lupeol linoleate, lupeol palmitate and α-amyrin linoleate are non-competitive inhibitors of trypsin (K_i values 7 μM, 10 μM and 16 μM, respectively). α-Amyrin linoleate is also a non-competitive inhibitor of chymotrypsin (K_i value 28 μM). Lupeol is a competitive inhibitor of both trypsin and chymotrypsin (K_i values 22 and 8 μM, respectively). α-Amyrin palmitate is a potent non-competitive inhibitor of chymotrypsin (K_i 6 μM). Lupeol, α-amyrin and the palmitic and linoleic acid esters of these compounds are ineffective or very weak as inhibitors of porcine pancreatic elastase and of Lucilia cuprina and Helicoverpa punctigera leucine aminopeptidases. These hydrophobic triterpenoids represent further examples of anti-inflammatory triterpenoids that are PKA inhibitors as well as being selective protease inhibitors.

Abbreviations

cAK:catalytic subunit of the cyclic AMP-dependent protein kinaseBAPNA:Nα-benzoyl-DL-arginine-p-nitroanilideBYPNA:N-benzoyl-L-tyrosine-p-nitroanilideCDPK:Ca²⁺-dependent protein kinaseLAP:leucine aminopeptidaseMLCK:myosin light chain kinasePES:N-succinyl-alanyl-alanyl-alanyl-p-nitroanilidePKA:cyclic AMP-dependent protein kinasePKC:Ca²⁺- and phospholipid-dependent protein kinase CTLCK:N-α-p-tosyl-L-lysinylchloromethyl ketone (1-chloro-3-tosylamido-7-amino-L-2-heptanone)TPCK:N-tosyl-L-phenylalanylchloromethyl ketone [L-(1-tosylamido-2-phenyl)ethylchloromethyl ketone]

Key words

Lupeol - α-amyrin - triterpenoids - protease inhibitors

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