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Synthesis and Structure Determination of µ-Conotoxin PIIIA Isomers with Different Disulfide Connectivities
Published on: October 2, 2018
Synthesis and conformational analysis of efrapeptins
Sven Weigelt1, Thomas Huber, Frank Hofmann
1Department of Chemistry, Bielefeld University, P. O. Box 100131, 33501 Bielefeld, Germany.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|December 8, 2011
Summary
Efrapeptins and neo-efrapeptins are peptide antibiotics that inhibit F(1)-ATPase, showing potential as antitumor and antimalaria agents. Their helical structures, particularly the 3(10)-helix in efrapeptin C, were confirmed through spectroscopic and modeling studies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Structural Biology
Background:
- The efrapeptin and neo-efrapeptin families are peptide antibiotics derived from fungi, known for inhibiting F(1)-ATPase.
- These peptides exhibit potential in treating cancer, malaria, and insect-borne diseases.
- They are characterized by unique structural features, including C(α)-dialkyl amino acids, β-alanine, pipecolic acid residues, and a cationic heterocyclic cap.
Purpose of the Study:
- To synthesize efrapeptins C-G and analogues using α-azido carboxylic acids.
- To investigate the inhibitory activity of synthesized compounds against F(1)-ATPase.
- To elucidate the solution-state conformation of these peptides using various spectroscopic techniques and molecular modeling.
Main Methods:
- Peptide synthesis utilizing α-azido carboxylic acids as masked amino acid precursors.
- Enzyme inhibition assays to determine activity against F(1)-ATPase.
- Spectroscopic analyses including electronic CD, FT-IR, and Vibrational CD (VCD) spectroscopy.
- Nuclear Magnetic Resonance (NMR) spectroscopy and molecular modeling for detailed conformational analysis, including residual dipolar couplings (RDC).
Main Results:
- All synthesized efrapeptins and analogues demonstrated inhibitory activity against F(1)-ATPase.
- Spectroscopic studies indicated that efrapeptins and most analogues adopt helical conformations in solution.
- VCD and NMR/molecular modeling studies confirmed a predominant 3(10)-helical structure for efrapeptin C.
Conclusions:
- The synthesized efrapeptins and analogues retain F(1)-ATPase inhibitory activity.
- The 3(10)-helical conformation is a key structural feature of efrapeptin C in solution.
- These findings contribute to understanding the structure-activity relationship of efrapeptins for potential therapeutic applications.
