Design and Biophysical Characterization of Novel Polycationic ϵ-Peptides for DNA Compaction and Delivery

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Abstract

Design and solid-phase synthesis of novel and chemically defined linear and branched -oligo( l-lysines) (denoted -K n, where n is the number of lysine residues) and their alpha-substituted homologues (epsilon-(R)K10, epsilon-(Y)K10, epsilon-(L)K10, epsilon-(YR)K10, and epsilon-(LYR)K10) for DNA compaction and delivery are reported. The ability to condense viral (T2 and T4) and plasmid DNA as well as the size of -peptide DNA complexes under different conditions was investigated with static and dynamic light scattering, isothermal titration calorimetry, and fluorescence microscopy. Nanoparticle diameters varied from 100 to 150 and 375 to 550 nm for plasmid and T4 DNA peptide complexes, respectively. Smaller sizes were observed for oligo(L-lysines) compared to alpha-poly( L-lysine). The linear -oligo-lysines are less toxic and epsilon-(LYR)K10 showed higher transfection efficiency in HeLa cells than corresponding controls. The results also demonstrate that with a branched design having pendent groups of short alpha-oligopeptides, improved transfection can be achieved. This study supports the hypothesis that available alpha-oligolysine derived systems would potentially have more favorable delivery properties if they are based instead on epsilon-oligo( L-lysines). The flexible design and unambiguous synthesis that enables variation of pendent groups holds promise for optimization of such -peptides to achieve improved DNA compaction and delivery.

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