DNA Cleaving “Tandem-Array” Metallopeptides Activated With KHSO5: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds

Author(s): Mark A. Lewis, Katie M. Williams, Ya-Yin Fang, Franklin A. Schultz, Eric C. Long.

Journal Name:Current Bioactive Compounds

Volume 10 , Issue 1 , 2014

Abstract:

Amino terminal peptides of the general form Gly-Gly-His have been used to introduce single sites of metal binding and redox activity into a wide range of biomolecules to create bioactive compounds and conjugates capable of substrate oxidation. We report here that Gly-Gly-His-like peptides linked in a tandem fashion can also be generated leading to multi-metal binding arrays. While metal binding by the native Gly-Gly-His motif (typically to Cu2+, Ni2+, or Co2+) requires a terminal peptide amine ligand, previous work has demonstrated that an ornithine (Orn) residue can be substituted for the terminal Gly residue to allow solid-phase peptide synthesis to continue via the side chain N-δ. This strategy thus frees the Orn residue N-α for metal binding and permits placement of a Gly-Gly-His-like metal binding domain at any location within a linear, synthetic peptide chain. As we show here, this strategy also permits the assembly of tandem arrays of metal binding units in linear peptides of the form: NH2-Gly-Gly-His-[(δ)-Orn-Gly-His]n-(δ)-Orn-Gly-His- CONH2 (where n = 0, 1, and 2). Metal binding titrations of these tandem arrays monitored by UV-vis and ESI-MS indicated that they bind Cu2+, Ni2+, or Co2+ at each available metal binding site. Further, it was found that these systems retained their ability to modify DNA oxidatively and to an extent greater than their parent M(II)•Gly-Gly-His. These findings suggest that the tandem array metallopeptides described here may function with increased efficiency as “next generation” appendages in the design of bioactive compounds and conjugates.

Keywords: DNA cleavage, metallopeptide, Gly-Gly-His, metal binding peptide.

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Article Details

VOLUME: 10
ISSUE: 1
Year: 2014
Page: [13 - 20]
Pages: 8
DOI: 10.2174/157340721001140724150901