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

Louic S. Vermeer, Yun Lan, Vincenzo Abbate, Emrah Ruh, Tam T. Bui, Louise J. Wilkinson, Tokuwa Kanno, Elmira Jumagulova, Justyna Kozlowska, Jayneil Patel, Caitlin A. McIntyre, W. C. Yam, Kit Hang Siu, R. Andrew Atkinson, Jenny K.W. Lam, Sukhvinder S. Bansal, Alex F. Drake, Graham H. Mitchell, A. James Mason

Research output: Journal article publicationJournal articleAcademic researchpeer-review

54 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)34120-34133
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number41
DOIs
Publication statusPublished - 5 Oct 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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