Affiliation:
1. Department of Chemical Sciences University of Padova Padova Italy
2. Chemistry Department, Faculty of Science Ain Shams University Cairo Abbassia 11566 Egypt
3. Padova Unit, CNR Institute of Biomolecular Chemistry University of Padova Padova Italy
Abstract
Peptaibols are naturally occurring, antimicrobial peptides endowed with well‐defined helical conformations and resistance to proteolysis. Both features stem from the presence in their sequence of several, Cα‐tetrasubstituted, α‐aminoisobutyric acid (Aib) residues. Peptaibols interact with biological membranes, usually causing their leakage. All of the peptaibol–membrane interaction mechanisms proposed so far begin with peptide aggregation or accumulation. The long‐length alamethicin, the most studied peptaibol, acts by forming pores in the membranes. Conversely, the carpet mechanism has been claimed for short‐length peptaibols, such as trichogin. The mechanism of medium‐length peptaibols is far less studied, and this is partly due to the difficulties of their synthesis. They are believed to perturb membrane permeability in different ways, depending on the membrane properties. The present work focuses on pentadecaibin, a recently discovered, medium‐length peptaibol. In contrast to the majority of its family members, its sequence does not comprise hydroxyprolines or prolines, and its helix is not kinked. A reliable and effective synthesis procedure is described that allowed us to produce also two shorter analogs. By a combination of techniques, we were able to establish a 3D‐structure–activity relationship. In particular, the membrane activity of pentadecaibin heavily depends on the presence of three consecutive Aib residues that are responsible for the clear, albeit modest, amphiphilic character of its helix. The shortest analog, devoid of two of these three Aib residues, preserves a well‐defined helical conformation, but not its amphipathicity, and loses almost completely the ability to cause membrane leakage. We conclude that pentadecaibin amphiphilicity is probably needed for the peptide ability to perturb model membranes.
Funder
Università degli Studi di Padova
Subject
Organic Chemistry,Drug Discovery,Pharmacology,Molecular Biology,Molecular Medicine,General Medicine,Biochemistry,Structural Biology
Cited by
2 articles.
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