Impact of Tryptophan Positional Isomerism on Physicochemical and Biological Properties: A Case Study Using Gramicidin A Analogs.

ABSTRACT: Tryptophan (Trp) displays unique physicochemical properties due to its C3-substituted indole ring, containing a hydrophobic benzene ring and a hydrophilic N-H bond. Herein, we synthetically incorporated five Trp positional isomers with C2/4/5/6/7-substituted indoles in place of the Trp of residue 11 in gramicidin A, a 15-mer linear peptidic natural product. Gramicidin A conducts monovalent cations across the cell membrane and exhibits potent toxicity against both bacterial and mammalian cells. Our functional evaluation of the five analogs revealed that positional isomerism controlled the overall hydrophobicity and biological activities for the first time. Most importantly, we found that the hydrophobicity of the analogs correlated with the potency of mammalian cytotoxicity but not with the

SUBMITTER: Migita T 

PROVIDER: S-EPMC12648344 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature