Cyanopeptolins with Trypsin and Chymotrypsin Inhibitory Activity from the Cyanobacterium Nostoc edaphicum CCNP1411

Abstract

Cyanopeptolins (CPs) are one of the most frequently occurring cyanobacterial peptides, many of which are inhibitors of serine proteases. Some CP variants are also acutely toxic to aquatic organisms, especially small crustaceans. In this study, thirteen CPs, including twelve new variants, were detected in the cyanobacterium Nostoc edaphicum CCNP1411 isolated from the Gulf of Gdańsk (southern Baltic Sea). Structural elucidation was performed by tandem mass spectrometry with verification by NMR for CP962 and CP985. Trypsin and chymotrypsin inhibition assays confirmed the significance of the residue adjacent to 3-amino-6-hydroxy-2-piperidone (Ahp) for the activity of the peptides. Arginine-containing CPs (CPs-Arg2) inhibited trypsin at low IC50 values (0.24–0.26 µM) and showed mild activity against chymotrypsin (IC50 3.1–3.8 µM), while tyrosine-containing CPs (CPs-Tyr2) were selectively and potently active against chymotrypsin (IC50 0.26 µM). No degradation of the peptides was observed during the enzyme assays. Neither of the CPs were active against thrombin, elastase or protein phosphatase 1. Two CPs (CP962 and CP985) had no cytotoxic effects on MCF-7 breast cancer cells. Strong and selective activity of the new cyanopeptolin variants makes them potential candidates for the development of drugs against metabolic disorders and other diseases.

Nostoc edaphicum CCNP1411 from the Baltic Sea—A New Producer of Nostocyclopeptides

“…In this work, cyanopeptolin gene cluster was identified in N . edaphicum CCNP1411 and thirteen products of the genes were previously reported [ 6 ]. These peptides contain seven amino acids and a short fatty acid chain, and only one element of the structure, 3-amino-6-hydroxy-2-piperidone (Ahp), is conserved [ 6 ].…”

“…Secondary metabolites produced by cyanobacteria of the genus Nostoc (Nostocales) are characterized by a high variety of structures and biological activities [1][2][3][4][5][6]. On the basis of chemical structure, these compounds are mainly classified to peptides, polyketides, lipids, polysaccharides and alkaloids [7].…”

“…On the basis of chemical structure, these compounds are mainly classified to peptides, polyketides, lipids, polysaccharides and alkaloids [ 7 ]. Abundantly produced cyanopeptides with anticancer, antimicrobial, antiviral and enzyme-inhibiting activity, have attracted attention of many research groups [ 6 , 8 , 9 , 10 , 11 , 12 ]. Some of the metabolites, such as nostocyclopeptides (Ncps) or cryptophycins are exclusively produced by the cyanobacteria of the genus Nostoc ( Figure 1 A).…”

“…In our previous studies, Nostoc edaphicum CCNP1411 ( Figure 1 A) from the Baltic Sea was found to be a rich source of cyanopeptolins, the nonribosomal peptides with potent inhibitory activity against serine proteases [ 6 ]. In the current work, the potential of the strain to produce other bioactive metabolites was explored.…”

Computational Design of New Analogues from Lyngbyastatin-2 against Epidermal Growth Factor Receptor (EGFR) through Molecular Docking

“…Lyngbyastatins 4-10, a group of compounds were all described as elastase inhibitors [16,18,35] with an IC50 range from 0.03 (lyngbyastatin 4) to 210 μM (lyngbyastatin 9). Lyngbyastatins are also strong chymotrypsin inhibitors, but with less potency than elastase, IC50 = 0.3 μM [34,36]. Moreover, there have been no reports available so far anticancer activities by in silico methods.…”