Bioactivity of topologically confined gramicidin A dimers |
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Authors: | Kirtikumar B. Jadhav Claudia Stein Oliwia Makarewicz Gabriele Pradel Roman J. Lichtenecker Holger Sack Stefan H. Heinemann Hans-Dieter Arndt |
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Affiliation: | 1. Friedrich Schiller University Jena, Institute of Organic Chemistry and Macromolecular Chemistry, Humboldtstr. 10, D-07743 Jena, Germany;2. Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747 Jena, Germany;3. RWTH Aachen University, Division of Cellular and Applied Infection Biology, Worringerweg 1, D-52074 Aachen, Germany;4. Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany |
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Abstract: | The d-/l-peptide gramicidin A (gA) is well known as a pivotal ion channel model and shows a broad spectrum of bioactivities such as antibiosis, antimalarial activity, as well as hemolysis. We applied inter-chain disulfide bonds to constrain the conformational freedom of gA into parallel and antiparallel dimeric topologies. Albeit the constructs were not found to be monoconformational, CD- and IR-spectroscopic studies suggested that this strategy indeed restricted the conformational space of the d-/l-peptide construct, and that β-helical secondary structures prevail. Correlative testing of gA dimers in antimicrobial, antimalarial, and ion conduction assays suggested that the tail-to-tail antiparallel single stranded β6.3 helix dominantly mediates the bioactivity of gA. Other conformers are unlikely to contribute to these activities. From these investigations, only weakly ion conducting gA dimers were identified that retained nM antimalarial activity. |
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Keywords: | Gramicidin A Disulfide β helix Antibiotics |
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