Browsing by Author "Lewis, Mark A."

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    DNA Cleaving "Tandem-Array" Metallopeptides Activated With KHSO5: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds
    (Bentham Science, 2014) Lewis, Mark A.; Williams, Katie M.; Fang, Ya-Yin; Schultz, Franklin A.; Long, Eric C.; Department of Chemistry and Chemical Biology, School of Science
    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 Cu(2+), Ni(2+), or Co(2+)) 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 Cu(2+), Ni(2+), or Co(2+) 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.
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    DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics
    (American Society for Microbiology, 2016-11-21) Opperman, Timothy J.; Kwasny, Steven M.; Bo Li, Jessica; Lewis, Mark A.; Aiello, Daniel; Williams, John D.; Peet, Norton P.; Moir, Donald T.; Bowlin, Terry L.; Long, Eric C.; Chemistry and Chemical Biology, School of Science
    We previously reported the synthesis and biological activity of a series of cationic bis-indoles with potent, broad-spectrum antibacterial properties. Here, we describe mechanism of action studies to test the hypothesis that these compounds bind to DNA and that this target plays an important role in their antibacterial outcome. The results reported here indicate that the bis-indoles bind selectively to DNA at A/T-rich sites, which is correlated with the inhibition of DNA and RNA synthesis in representative Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) organisms. Further, exposure of E. coli and S. aureus to representative bis-indoles resulted in induction of the DNA damage-inducible SOS response. In addition, the bis-indoles were found to be potent inhibitors of cell wall biosynthesis; however, they do not induce the cell wall stress stimulon in S. aureus, suggesting that this pathway is inhibited by an indirect mechanism. In light of these findings, the most likely basis for the observed activities of these compounds is their ability to bind to the minor groove of DNA, resulting in the inhibition of DNA and RNA synthesis and other secondary effects.
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    Practice Makes Perfect: The Rest of the Story in Testicular Cancer as a Model Curable Neoplasm
    (American Society of Clinical Oncology, 2017-11-01) Tandstad, Torgrim; Kollmannsberger, Christian K.; Roth, Bruce J.; Jeldres, Claudio; Gillessen, Silke; Fizazi, Karim; Daneshmand, Siamak; Lowrance, William T.; Hanna, Nasser H.; Albany, Costantine; Foster, Richard; Cedermark, Gabriella Cohn; Feldman, Darren R.; Powles, Thomas; Lewis, Mark A.; Grimison, Peter Scott; Bank, Douglas; Porter, Christopher; Albers, Peter; De Santis, Maria; Srinivas, Sandy; Bosl, George J.; Nichols, Craig R.; Medicine, School of Medicine
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    Two distinct rotations of bithiazole DNA intercalation revealed by direct comparison of crystal structures of Co(III)•bleomycin A2 and B2 bound to duplex 5’-TAGTT sites
    (Elsevier, 2023-01-01) Goodwin, Kristie D.; Lewis, Mark A.; Long, Eric C.; Georgiadis, Millie M.; Chemistry and Chemical Biology, School of Science
    Bleomycins constitute a family of anticancer natural products that bind DNA through intercalation of a C-terminal tail/bithiazole moiety and hydrogen-bonding interactions between the remainder of the drug and the minor groove. The clinical utility of the bleomycins is believed to result from single- and double-strand DNA cleavage mediated by the HOO-Fe(III) form of the drug. The bleomycins also serve as a model system to understand the nature of complex drug-DNA interactions that may guide future DNA-targeted drug discovery. In this study, the impact of the C-terminal tail on bleomycin-DNA interactions was investigated. Toward this goal, we determined two crystal structures of HOO-Co(III)•BLMA2 “green” (a stable structural analogue of the active HOO-Fe(III) drug) bound to duplex DNA containing 5′-TAGTT, one in which the entire drug is bound (fully bound) and a second with only the C-terminal tail/bithiazole bound (partially bound). The structures reported here were captured by soaking HOO-Co(III)•BLMA2 into preformed host–guest crystals including a preferred DNA-binding site. While the overall structure of DNA-bound BLMA2 was found to be similar to those reported earlier at the same DNA site for BLMB2, the intercalated bithiazole of BLMB2 is “flipped” 180˚ relative to DNA-bound BLMA2. This finding highlights an unidentified role for the C-terminal tail in directing the intercalation of the bithiazole. In addition, these analyses identified specific bond rotations within the C-terminal domain of the drug that may be relevant for its reorganization and ability to carry out a double-strand DNA cleavage event.