Synthesis and characterization of cortinarins – cryptic cyclic peptides from mushrooms of the genus Cortinarius

Abstract

Cortinarins have been described as cyclic peptides from mushrooms of the genus Cortinarius, and brought into context with mushroom intoxication, particularly causing kidney damage. Herein we report the first total synthesis of the bicyclic peptides cortinarin A and B using iodine-mediated Trp–Cys cyclization to establish their characteristic tryptathionine bridge. Peptide atropisomers, termed ansamers, were observed and characterized by NMR spectroscopy and molecular dynamics simulations. Conformational analysis showed that cortinarins adopt β-turn structures. Furthermore, cortinarins induce similar effects like the peptide hormone arginine vasopressin on the localization of aquaporin-2 in renal principal cells, which regulates water and salt balance in the body, but with a different mode of action. This work thus provides synthetic access to the otherwise elusive cortinarins for biological evaluation and as potential lead compounds for the treatment of renal disorders.