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Conformational flexibility determines selectivity and antibacterial, antiplasmodial,andanticancer potency of cationic -αhelical peptides

Vermeer, LS and Lan, Y and Abbate, V and Ruh, E and Bui, TT and Wilkinson, LJ and Kanno, T and Jumagulova, E and Kozlowska, J and Patel, J and McIntyre, CA and Yam, WC and Siu, G and Atkinson, RA and Lam, JKW and Bansal, SS and Drake, AF and Mitchell, GH and Mason, AJ (2012) 'Conformational flexibility determines selectivity and antibacterial, antiplasmodial,andanticancer potency of cationic -αhelical peptides.' Journal of Biological Chemistry, 287 (41). 34120 - 34133. ISSN 0021-9258

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We used a combination of fluorescence, circular dichroism (CD), and NMR spectroscopies in conjunction with size exclusion chromatography to help rationalize the relative antibacterial, antiplasmodial, and cytotoxic activities of a series of proline-free and proline-containing model antimicrobial peptides (AMPs) in terms of their structural properties. When compared with proline-free analogs, proline-containing peptides had greater activity against Gram-negative bacteria, two mammalian cancer cell lines, and intraerythrocytic Plasmodium falciparum, which they were capable of killing without causing hemolysis. In contrast, incorporation of proline did not have a consistent effect on peptide activity against Mycobacterium tuberculosis. In membrane-mimicking environments, structures with high α-helix content were adopted by both proline-free and proline-containing peptides. In solution, AMPs generally adopted disordered structures unless their sequences comprised more hydrophobic amino acids or until coordinating phosphate ions were added. Proline-containing peptides resisted ordering induced by either method. The roles of the angle subtended by positively charged amino acids and the positioning of the proline residues were also investigated. Careful positioning of proline residues in AMP sequences is required to enable the peptide to resist ordering and maintain optimal antibacterial activity, whereas varying the angle subtended by positively charged amino acids can attenuate hemolytic potential albeit with a modest reduction in potency. Maintaining conformational flexibility improves AMP potency and selectivity toward bacterial, plasmodial, and cancerous cells while enabling the targeting of intracellular pathogens. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Item Type: Article
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Graham Mitchell
Date Deposited: 23 Mar 2015 20:01
Last Modified: 14 Aug 2019 11:15

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