Protease Inhibitors from a Water Bloom of the Cyanobacterium Microcystis aeruginosa

Bioassay-guided fractionation of the polar extract of a Microcystis aeruginosa water bloom biomass yielded 10 micropeptins and one anabaenopeptin. Eight of the micropeptins, micropeptins HU1069 (1), HU989 (2), HU1021 (3), HU1041 (4), HU975 (5), HU895A (6), HU909 (7), and HU895B (8), are new, while two, micropeptins 478-A (10) and 478-B (11), were previously isolated from a bloom of M. aeruginosa from Japan. The new anabaenopeptin HU892 (9) belongs to the relatively rare subgroup, presenting an aliphatic amino acid at the carboxylic end of the peptide and N-methylhomoaromatic amino acid at the second position. The structures of the compounds were determined by ID and 2D NMR techniques and mass spectrometric data. The isolated micropeptins inhibited trypsin with IC50'S that varied between 0.7 and 5.2 mu M and unexpectedly inhibited chymotrypsin with IC50's that varied between 2.8 and 72.0 mu M. The SAR of these micropeptins is discussed.