Abstract
Aeruginosamides (AEGs) are classified as cyanobactins, ribosomally synthesized peptides with post-translational modifications. They have been identified in cyanobacteria of genera Microcystis, Oscillatoria, and Limnoraphis. In this work, the new data on the in vitro activities of three AEG variants, AEG A, AEG625 and AEG657, and their interactions with metabolic enzymes are reported. Two aeruginosamides, AEG625 and AEG657, decreased the viability of human breast cancer cell line T47D, but neither of the peptides was active against human liver cancer cell line Huh7. AEGs also did not change the expression of MIR92b-3p, but for AEG625, the induction of oxidative stress was observed. In the presence of a liver S9 fraction containing microsomal and cytosolic enzymes, AEG625 and AEG657 showed high stability. In the same assays, quick removal of AEG A was recorded. The peptides had mild activity against three cytochrome P450 enzymes, CYP2C9, CYP2D6 and CYP3A4, but only at the highest concentration used in the study (60 µM). The properties of AEGs, i.e., cytotoxic activity and in vitro interactions with important metabolic enzymes, form a good basis for further studies on their pharmacological potential.
Highlights
Cyanobacterial metabolites are frequently used as a starting material for the development of new drugs [1,2,3,4]
A derivative of dolastatin 10, a potent microtubule inhibitor produced by marine cyanobacterium Symploca, was approved for the treatment of Hodgkin’s lymphoma [5,6]
Another bioactive compound produced by Symploca, is explored as an anticancer drug that acts by inhibiting class I histone deacetylases (HDACs) [7]
Summary
Cyanobacterial metabolites are frequently used as a starting material for the development of new drugs [1,2,3,4]. A derivative of dolastatin 10, a potent microtubule inhibitor produced by marine cyanobacterium Symploca (originally isolated from sea hare Dolabella auricularia), was approved for the treatment of Hodgkin’s lymphoma [5,6] Largazole, another bioactive compound produced by Symploca, is explored as an anticancer drug that acts by inhibiting class I histone deacetylases (HDACs) [7]. Cyanovirin-N, a lectin produced by Nostoc ellipsosporum, acts as an antiviral agent It prevents infection by blocking the interaction between human immunodeficiency virus (HIV) gp120 and the cell-associated CD4 receptor [9]. Another lectin, microvirin, shows similar activity, but has a simpler structure and better safety profile [10]. For this purpaonsdeA, tEhGe6i5n7 v(Fiitgruoreac1t)i,vaigtaieinsstobf rteharset ecainscoelratceeldlsa(eTr4u7Dg)inaonsdalmiveidr ecasn, cAerEcGellAs ,(HAuEhG7)625 and AEG657w(eFreigteusrteed1. )L,uacigfearianssetrebproeratesrtacsasanycsewr ecreelulsse(dTt4o7eDxa)mainnedwlihveethrecr aAnEcGesraccet ltlhsro(uHguh h7) were tested. tLheurceigfeurlaatsioenroefpsopretceifricamssiRaNysAworetrherouusgehdthteoinedxuacmtioinneofwoxhideathtiveer sAtrEesGs.sInaacdtdtihtiroonu, gh the regulatiotno ogafisnpseocmifie cknmowiRleNdgAe oonr tthheropuogsshibtlehebeihnadvuiocutrioonf AoEfGosxuidnadteirvpehsytsrieoslosg.icInal acodnddiit-ion, to gain some knowledge on the possible behaviour of AEGs under physiological conditions, we studied the metabolic stability of peptides in the liver S9 fraction containing microsomal and cytosolic enzymes, and the effect of the AEGs on the activity of three cytochrome P450 enzymes CYP2C9, CYP2D6 and CYP3A4
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