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Berlin Brandenburg

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  • 1
    Language: English
    In: Journal of the American Chemical Society, 29 June 2011, Vol.133(25), pp.9912-22
    Description: A series of compounds that target reactive metal chelates to the HIV-1 Rev response element (RRE) mRNA have been synthesized. Dissociation constants and chemical reactivity toward HIV RRE RNA have been determined and evaluated in terms of reduction potential, coordination unsaturation, and overall charge associated with the metal-chelate-Rev complex. Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), diethylenetriaminepentaacetic acid (DTPA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were linked to a lysine side chain of a Rev-derived peptide by either EDC/NHS or isothiocyanate coupling. The resulting chelate-Rev (EDTA-Rev, DTPA-Rev, NTA-Rev, and DOTA-Rev) conjugates were used to form coordination complexes with Fe(2+), Co(2+), Ni(2+), and Cu(2+) such that the arginine-rich Rev peptide could mediate localization of the metal chelates to the Rev peptide's high-affinity mRNA binding partner, RRE stem loop IIB. Metal complexes of the extended peptides GGH-Rev and KGHK-Rev, which also contain N-terminal peptidic chelators (ATCUN motifs), were studied for comparison. A fluorescence titration assay revealed high-affinity RRE RNA binding by all 22 metal-chelate-Rev species, with K(D) values ranging from ~0.2 to 16 nM, indicating little to no loss of RNA affinity due to the coupling of the metal chelates to the Rev peptide. Dissociation constants for binding at a previously unobserved low-affinity site are also reported. Rates of RNA modification by each metal-chelate-Rev species were determined and varied from ~0.28 to 4.9 nM/min but were optimal for Cu(2+)-NTA-Rev. Metal-chelate reduction potentials were determined and varied from -228 to +1111 mV vs NHE under similar solution conditions, allowing direct comparison of reactivity with redox thermodynamics. Optimal activity was observed when the reduction potential for the metal center was poised between those of the two principal co-reagents for metal-promoted formation of reactive oxygen species: E°(ascorbate/ascorbyl radical) = -66 mV and E°(H(2)O(2)/hydroxyl radical) = 380 mV. Given the variety of oxidative activities of these metal complexes and their high-affinity binding to the targeted RRE mRNA following coupling to the Rev peptide, this class of metal-chelate-Rev derivatives constitutes a promising step toward development of multiple-turnover reagents for selective eradication of HIV-1 RRE mRNA.
    Keywords: Anti-HIV Agents -- Chemical Synthesis ; Chelating Agents -- Pharmacology ; Gene Products, Rev -- Genetics ; HIV -- Genetics ; RNA, Viral -- Drug Effects ; Response Elements -- Drug Effects
    ISSN: 00027863
    E-ISSN: 1520-5126
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  • 2
    Language: English
    In: Journal of the American Chemical Society, 05 October 2011, Vol.133(39), pp.15613-26
    Description: A library of complexes that included iron, cobalt, nickel, and copper chelates of cyclam, cyclen, DOTA, DTPA, EDTA, tripeptide GGH, tetrapeptide KGHK, NTA, and TACN was evaluated for DNA nuclease activity, ascorbate consumption, superoxide and hydroxyl radical generation, and reduction potential under physiologically relevant conditions. Plasmid DNA cleavage rates demonstrated by combinations of each complex and biological co-reactants were quantified by gel electrophoresis, yielding second-order rate constants for DNA(supercoiled) to DNA(nicked) conversion up to 2.5 × 10(6) M(-1) min(-1), and for DNA(nicked) to DNA(linear) up to 7 × 10(5) M(-1) min(-1). Relative rates of radical generation and characterization of radical species were determined by reaction with the fluorescent radical probes TEMPO-9-AC and rhodamine B. Ascorbate turnover rate constants ranging from 3 × 10(-4) to 0.13 min(-1) were determined, although many complexes demonstrated no measurable activity. Inhibition and Freifelder-Trumbo analysis of DNA cleavage supported concerted cleavage of dsDNA by a metal-associated reactive oxygen species (ROS) in the case of Cu(2+)(aq), Cu-KGHK, Co-KGHK, and Cu-NTA and stepwise cleavage for Fe(2+)(aq), Cu-cyclam, Cu-cyclen, Co-cyclen, Cu-EDTA, Ni-EDTA, Co-EDTA, Cu-GGH, and Co-NTA. Reduction potentials varied over the range from -362 to +1111 mV versus NHE, and complexes demonstrated optimal catalytic activity in the range of the physiological redox co-reactants ascorbate and peroxide (-66 to +380 mV).
    Keywords: Chelating Agents -- Pharmacology ; DNA Cleavage -- Drug Effects ; Deoxyribonucleases -- Pharmacology ; Metals, Heavy -- Pharmacology
    ISSN: 00027863
    E-ISSN: 1520-5126
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  • 3
    Language: English
    In: Journal of the American Chemical Society, 22 February 2012, Vol.134(7), pp.3396-410
    Description: A series of compounds that target reactive transition-metal chelates to somatic angiotensin converting enzyme (sACE-1) have been synthesized. Half-maximal inhibitory concentrations (IC(50)) and rate constants for both inactivation and cleavage of full-length sACE-1 have been determined and evaluated in terms of metal chelate size, charge, reduction potential, coordination unsaturation, and coreactant selectivity. Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and tripeptide GGH were linked to the lysine side chain of lisinopril by 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride/N-hydroxysuccinimide coupling. The resulting amide-linked chelate-lisinopril (EDTA-lisinopril, NTA-lisinopril, DOTA-lisinopril, and GGH-lisinopril) conjugates were used to form coordination complexes with iron, cobalt, nickel, and copper, such that lisinopril could mediate localization of the reactive metal chelates to sACE-1. ACE activity was assayed by monitoring cleavage of the fluorogenic substrate Mca-RPPGFSAFK(Dnp)-OH, a derivative of bradykinin, following preincubation with metal chelate-lisinopril compounds. Concentration-dependent inhibition of sACE-1 by metal chelate-lisinopril complexes revealed IC(50) values ranging from 44 to 4500 nM for Ni-NTA-lisinopril and Ni-DOTA-lisinopril, respectively, versus 1.9 nM for lisinopril. Stronger inhibition was correlated with smaller size and lower negative charge of the attached metal chelates. Time-dependent inactivation of sACE-1 by metal chelate-lisinopril complexes revealed a remarkable range of catalytic activities, with second-order rate constants as high as 150,000 M(-1) min(-1) (Cu-GGH-lisinopril), while catalyst-mediated cleavage of sACE-1 typically occurred at much lower rates, indicating that inactivation arose primarily from side chain modification. Optimal inactivation of sACE-1 was observed when the reduction potential for the metal center was poised near 1000 mV, reflecting the difficulty of protein oxidation. This class of metal chelate-lisinopril complexes possesses a range of high-affinity binding to ACE, introduces the advantage of irreversible catalytic turnover, and marks an important step toward the development of multiple-turnover drugs for selective inactivation of sACE-1.
    Keywords: Angiotensin-Converting Enzyme Inhibitors -- Chemistry ; Chelating Agents -- Chemistry ; Lisinopril -- Analogs & Derivatives ; Peptidyl-Dipeptidase A -- Metabolism ; Transition Elements -- Chemistry
    ISSN: 00027863
    E-ISSN: 1520-5126
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  • 4
    In: Journal of Physiology, 15 October 2013, Vol.591(20), pp.4953-4953
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2013.263004/abstract Byline: Michael J. Joyner(1) ***** No abstract is available for this article. ***** Author Affiliation: (1)Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    Keywords: Resveratrol;
    ISSN: 0022-3751
    E-ISSN: 1469-7793
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  • 5
    Article
    Article
    Language: English
    In: Journal of Physiology, Dec, 2011, Vol.589(24), p.5927(2)
    Description: To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1113/jphysiol.2011.223792 Byline: Michael J. Joyner (1) Author Affiliation: (1)Department of Anaesthesiology, Mayo Clinic, Rochester, MN 55905, USA Article note: Email: joyner.michael@mayo.edu
    ISSN: 0022-3751
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  • 6
    In: Journal of Physiology, August 2011, Vol.589(16), pp.3905-3906
    Description: To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1113/jphysiol.2011.214973 Byline: Michael J. Joyner (1) Author Affiliation: (1)Department of Anaesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Article note: Email: joyner.michael@mayo.edu
    Keywords: Female–Genetics ; Humans–Metabolism ; Male–Physiopathology ; Muscle Proteins–Physiopathology ; Muscle, Skeletal–Physiopathology ; Muscular Atrophy–Physiopathology ; Muscle Proteins;
    ISSN: 0022-3751
    E-ISSN: 1469-7793
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  • 7
    In: Journal of Physiology, 01 October 2011, Vol.589(19), pp.4803-4803
    Description: To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1113/jphysiol.2011.218792 Byline: Michael J. Joyner (1) Author Affiliation: (1)The Mayo Clinic, Department of Anesthesiology, 200 First Street SW Rochester, MN 55905, USA Article note: Email: joyner.michael@mayo.edu
    Keywords: Anatomy & Physiology;
    ISSN: 0022-3751
    E-ISSN: 1469-7793
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  • 8
    In: Journal of Physiology, 01 March 2011, Vol.589(5), pp.1005-1005
    Description: To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1113/jphysiol.2010.203893 Byline: Michael J. Joyner (1) Author Affiliation: (1)Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Article note: Email: joyner.michael@mayo.edu
    Keywords: Physiology;
    ISSN: 0022-3751
    E-ISSN: 1469-7793
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  • 9
    Language: English
    In: American Journal of Sociology, 09/2011, Vol.117(2), pp.710-712
    Keywords: Sociology & Social History;
    ISSN: 0002-9602
    E-ISSN: 1537-5390
    Source: CrossRef
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  • 10
    In: Medicine & Science in Sports & Exercise, 2011, Vol.43(4), pp.655-655
    Keywords: Physical Endurance -- Physiology ; Running -- Physiology;
    ISSN: 0195-9131
    E-ISSN: 15300315
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