Design,synthesis and evaluation of antimicrobial activity of N-terminal modified Leucocin A analogues |
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Authors: | Krishna Chaitanya Bodapati Rania Soudy Hashem Etayash Michael Stiles Kamaljit Kaur |
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Institution: | 1. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1;2. CanBiocin Inc., Edmonton, Alberta, Canada T5J 4P6 |
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Abstract: | Class IIa bacteriocins are potent antimicrobial peptides produced by lactic acid bacteria to destroy competing microorganisms. The N-terminal domain of these peptides consists of a conserved YGNGV sequence and a disulphide bond. The YGNGV motif is essential for activity, whereas, the two cysteines involved in the disulphide bond can be replaced with hydrophobic residues. The C-terminal region has variable sequences, and folds into a conserved amphipathic α-helical structure. To elucidate the structure–activity relationship in the N-terminal domain of these peptides, three analogues (1–3) of a class IIa bacteriocin, Leucocin A (LeuA), were designed and synthesized by replacing the N-terminal β-sheet residues of the native peptide with shorter β-turn motifs. Such replacement abolished the antibacterial activity in the analogues, however, analogue 1 was able to competitively inhibit the activity of native LeuA. Native LeuA (37-mer) was synthesized using native chemical ligation method in high yield. Solution conformation study using circular dichroism spectroscopy and molecular dynamics simulations suggested that the C-terminal region of analogue 1 adopts helical folding as found in LeuA, while the N-terminal region did not fold into β-sheet conformation. These structure–activity studies highlight the role of proper folding and complete sequence in the activity of class IIa bacteriocins. |
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Keywords: | Antimicrobial peptide Class IIa bacteriocins Leucocin A (LeuA) Solid phase peptide synthesis Native chemical ligation Antimicrobial activity Solution conformation Structure–activity relationships |
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