Structure of amatoxin analogues
Wiley InterScience Backfile Collection 1832-2000
Chemistry and Pharmacology
The evaluation of peptide structures in solution is made feasible by the combined use of two-dimensional NMR in the laboratory (NOESY) and rotating frames (ROESY), and by the use of molecular dynamics calculations. The present paper describes how both the NMR method and molecular dynamics calculations were applied to very rigid synthetic bicyclic peptides that are analogues of natural amatoxins. The NMR theory, which allows the estimate of interatomic distances between interacting nuclei, is briefly discussed. The experimental data were compared with those of known solid-state structures. Three amatoxin analogues have been examined. Of these, one is biologically active (S-deoxo γ[R] OH-Ile3-amaninamide) and its structure in the solid state has recently been worked out. The second and third analogues (S-deoxo-Ile3 -Ala5-amaninamide and S-deoxo-D-Ile3 -amaninamide, respectively) are inactive and their solid-state structures are unknown. The data presented confirm the authors' previous hypothesis that lack of biological activity of S-deoxo-Ile3-Ala5- amaninamide is due to the masking of the tryptophan ring by the methyl group of L-Ala and not to massive conformational changes of the analogue.
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