The efrapeptin family of peptide antibiotics produced by the fungus Tolypocladium niveum, and the neo-efrapeptins
from the fungus Geotrichum candidum are inhibitors of F1-ATPase with promising antitumor, antimalaria, and insecticidal
activity. They are rich in Cα-dialkyl amino acids (Aib, Iva, Acc) and contain one β-alanine and several pipecolic
acid residues. The C-terminus bears an unusual heterocyclic cationic cap.
The efrapeptins C—G and three analogs of efrapeptin C were synthesized using α-azido carboxylic acids as masked
amino acid derivatives. All compounds display inhibitory activity toward F1-ATPase. The solution conformation
of the peptides was investigated with electronic CD spectroscopy, FT-IR spectroscopy, and VCD spectroscopy.
All efrapeptins and efrapeptin analogs were shown to adopt helical conformations in solution. In the case of
efrapeptin C VCD spectra proved that a 310-helix prevails. In addition, efrapeptin C was conformationally studied
in detail with NMR and molecular modelling. Besides NOE distance restraints, residual dipolar couplings (RDC) observed
upon partial alignment with stretched PDMS gels were used for the conformational analysis and confirmed the 310-helical conformation.
S. Weigelt, T. Huber, F. Hofmann, M. Jost, M. Ritzefeld, B. Luy, C. Freudenberger, Z. Majer, E. Vass, J.C. Greie, L. Panella, B. Kaptein, Q.B. Broxterman, H. Kessler, K. Altendorf, M. Hollósi, N. Sewald,
Chem. Eur. J. 2012, 18, 478–487.