title: Bioactivity of topologically confined gramicidin A dimers.
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 β6.3helix 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.
authors.affiliation: Friedrich Schiller University Jena, Institute of Organic Chemistry and Macromolecular Chemistry, Humboldtstr. 10, D-07743 Jena, Germany.
authors.forename: Kirtikumar B
authors.initials: KB
authors.lastname: Jadhav
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747 Jena, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stein
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747 Jena, Germany.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Makarewicz
authors.affiliation: RWTH Aachen University, Division of Cellular and Applied Infection Biology, Worringerweg 1, D-52074 Aachen, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.affiliation: Friedrich Schiller University Jena, Institute of Organic Chemistry and Macromolecular Chemistry, Humboldtstr. 10, D-07743 Jena, Germany.
authors.forename: Roman J
authors.initials: RJ
authors.lastname: Lichtenecker
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sack
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.affiliation: Friedrich Schiller University Jena, Institute of Organic Chemistry and Macromolecular Chemistry, Humboldtstr. 10, D-07743 Jena, Germany. Electronic address: hd.arndt@uni-jena.de.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Arndt
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D002942:Circular Dichroism; D019281:Dimerization; D004220:Disulfides / Q000138:chemical synthesis / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006096:Gramicidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006461:Hemolysis; D008567:Membranes, Artificial; D008968:Molecular Conformation; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000962:Antimalarials; D004220:Disulfides; D008567:Membranes, Artificial; D006096:Gramicidin; C032275:N-acetylgramicidin
keywords: Antibiotics; Disulfide; Gramicidin A; d-/l-Peptides; β helix