title: Conformational flexibility determines selectivity and antibacterial, antiplasmodial, and anticancer potency of cationic α-helical peptides.
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.
authors.affiliation: Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: Louic S
authors.initials: LS
authors.lastname: Vermeer
authors.forename: Yun
authors.initials: Y
authors.lastname: Lan
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Abbate
authors.forename: Emrah
authors.initials: E
authors.lastname: Ruh
authors.forename: Tam T
authors.initials: TT
authors.lastname: Bui
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Wilkinson
authors.forename: Tokuwa
authors.initials: T
authors.lastname: Kanno
authors.forename: Elmira
authors.initials: E
authors.lastname: Jumagulova
authors.forename: Justyna
authors.initials: J
authors.lastname: Kozlowska
authors.forename: Jayneil
authors.initials: J
authors.lastname: Patel
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: McIntyre
authors.forename: W C
authors.initials: WC
authors.lastname: Yam
authors.forename: Gilman
authors.initials: G
authors.lastname: Siu
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Atkinson
authors.forename: Jenny K W
authors.initials: JK
authors.lastname: Lam
authors.forename: Sukhvinder S
authors.initials: SS
authors.lastname: Bansal
authors.forename: Alex F
authors.initials: AF
authors.lastname: Drake
authors.forename: Graham H
authors.initials: GH
authors.lastname: Mitchell
authors.forename: A James
authors.initials: AJ
authors.lastname: Mason
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D010963:Plasmodium falciparum / Q000254:growth & development*; D017433:Protein Structure, Secondary
chemical_list: D000900:Anti-Bacterial Agents; D000962:Antimalarials; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents