Synthesis, and Structural and Biological Studies of Efrapeptin C Analogues

• Published in: Chemistry & biodiversity Vol. 4; no. 6; pp. 1170 - 1182
• Main Authors: Jost, Micha, Weigelt, Sven, Huber, Thomas, Majer, Zsuzsanna, Greie, Jörg-Christian, Altendorf, Karlheinz, Sewald, Norbert
• Format: Journal Article
• Language: English
• Published: Zürich WILEY-VCH Verlag 01.06.2007; WILEY‐VCH Verlag
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; ATPase Inhibitors; CD Spectroscopy; Circular Dichroism; Efrapeptin C; Escherichia coli - drug effects; Models, Molecular; Molecular recognition; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Protein Structure, Secondary; Total synthesis; X-Ray Diffraction
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.200790103

A series of analogues of efrapeptin C (1), with variations in the central tripeptide epitope (positions 6–8), were prepared by a combination of solid‐ and solution‐phase peptide syntheses. The conformations of the modified compounds 2–6 were investigated by circular‐dichroism (CD) spectroscopy to differentiate between 310‐ and α‐helical secondary structures. The inhibitory activities of the new compounds towards F1‐ATPase from E. coli were determined. The modified congeners 3–5 were less active by one order of magnitude compared to 1 (Ki 10 μM), and 6 was completely inactive. Our experiments demonstrate that the flexible, central tripeptide epitope, comprising positions 6–8 in 1, is crucial for molecular recognition, even slight sequence modifications being hardly tolerated.