Conformational flexibility determines selectivity and antibacterial, antiplasmodial, and anticancer potency of cationic α-helical peptides.

J Biol Chem 2012 Oct 6;287(41):34120-33. Epub 2012 Aug 6.

Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.

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.

Download full-text PDF

Source
http://repository.essex.ac.uk/13312/1/J.%20Biol.%20Chem.-201
Web Search
http://www.jbc.org/lookup/doi/10.1074/jbc.M112.359067
Publisher Site
http://dx.doi.org/10.1074/jbc.M112.359067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464521PMC
October 2012
28 Reads

Publication Analysis

Top Keywords

amino acids
12
proline-containing peptides
12
angle subtended
8
antibacterial antiplasmodial
8
proline residues
8
proline-free proline-containing
8
subtended positively
8
conformational flexibility
8
positively charged
8
charged amino
8
positioning proline
8
peptides
5
incorporation proline
4
maintain optimal
4
contrast incorporation
4
proline consistent
4
hemolysis contrast
4
optimal antibacterial
4
antibacterial activity
4
ordering maintain
4

Similar Publications