Delivering Structural Information on the Polar Face of Membrane-Active Peptides: 19F-NMR Labels with a Cationic Side Chain

• Published in: Angewandte Chemie 2016-11, Vol.128 (47), p.14815-14819
• Main Authors: Michurin, Oleg M., Afonin, Sergii, Berditsch, Marina, Daniliuc, Constantin G., Ulrich, Anne S., Komarov, Igor V., Radchenko, Dmytro S.
• Format: Article
• Language: eng ; ger
• Subjects: Aminosäuren; Antiinfectives and antibacterials; Cations; Chains; Chemistry; Constraints; Crystal structure; Design; Festkörper-19F-NMR-Spektroskopie; Fluor; Fluorine; Labels; Lysin; Lysine; Mathematical models; Molecular conformation; NMR; Nuclear magnetic resonance; Peptide; Peptides; Residues; Solid state
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201607161

Conformationally constrained non‐racemizing trifluoromethyl‐substituted lysine isosteres [(E)‐ and (Z)‐TCBLys] with charged side chains are presented as a new type of 19F‐NMR labels for peptide studies. Design of the labels, their synthesis, incorporation into peptides and experimental demonstration of their application for solid state NMR studies of membrane‐active peptides are described. A series of fluorine‐labeled analogues of the helical amphipathic antimicrobial peptide PGLa(Nle) was obtained, in which different lysine residues in the original peptide sequence were replaced, one at a time, by either (E)‐ or (Z)‐TCBLys. Antimicrobial activities of the synthesized analogues were practically the same as those of the parent peptide. The structural and orientational parameters of the helical PGLa(Nle) peptide in model bilayers, as determined using the novel labels confirmed and refined the previously known structure. (E)‐ and (Z)‐TCBLys, as a set of cationic 19F‐NMR labels, were shown to deliver structural information about the charged face of amphipathic peptides by solid state 19F‐NMR, previously inaccessible by this method. Ein Blick auf die dunkle Seite: Eine Cyclobutan‐basierte α‐Aminosäure wurde als die erste 19F‐NMR‐Markierung mit einer geladenen Seitenkette entworfen. Zwei Diastereomere der Aminosäure wurden genutzt, um Festkörper‐NMR‐Daten der zuvor unzugänglichen kationischen Seite des Membranpeptids PGLa(Nle) zu gewinnen. Die Markierung zeigt Ähnlichkeit zu Lysin, was ihre Verwendung in NMR‐Studien Lysin‐reicher Membranpeptide ermöglicht.