title: DNA Cleaving "Tandem-Array" Metallopeptides Activated With KHSO5: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds.
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 chainN-δ. This strategy thus frees the Orn residueN-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(wheren= 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.
authors.affiliation: Department of Chemistry & Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, Indiana 46202.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lewis
authors.affiliation: Department of Chemistry & Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, Indiana 46202.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Williams
authors.affiliation: Department of Biochemistry & Molecular Biology, Howard University, 520 W Street, NW, Washington, D. C. 20059.
authors.forename: Ya-Yin
authors.initials: YY
authors.lastname: Fang
authors.affiliation: Department of Chemistry & Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, Indiana 46202.
authors.forename: Franklin A
authors.initials: FA
authors.lastname: Schultz
authors.affiliation: Department of Chemistry & Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, Indiana 46202.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Long
keywords: DNA cleavage; Gly-Gly-His; metal binding peptide; metallopeptide