Anna F. A. Peacock
University of Birmingham
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Featured researches published by Anna F. A. Peacock.
Chemistry-an Asian Journal | 2008
Anna F. A. Peacock; Peter J. Sadler
The field of medicinal inorganic chemistry is rapidly advancing. In particular organometallic complexes have much potential as therapeutic and diagnostic agents. The carbon-bound and other ligands allow the thermodynamic and kinetic reactivity of the metal ion to be controlled and also provide a scaffold for functionalization. The establishment of structure-activity relationships and elucidation of the speciation of complexes under conditions relevant to drug testing and formulation are crucial for the further development of promising medicinal applications of organometallic complexes. Specific examples involving the design of ruthenium and osmium arene complexes as anticancer agents are discussed.
Nature Chemistry | 2012
Melissa L. Zastrow; Anna F. A. Peacock; Jeanne A. Stuckey; Vincent L. Pecoraro
Metal ions are an important part of many natural proteins, providing structural, catalytic and electron transfer functions. Reproducing these functions in a designed protein is the ultimate challenge to our understanding of them. Here, we present an artificial metallohydrolase, which has been shown by X-ray crystallography to contain two different metal ions – a Zn(II) ion which is important for catalytic activity and a Hg(II) ion which provides structural stability. This metallohydrolase displays catalytic activity that compares well with several characteristic reactions of natural enzymes. It catalyses p-nitrophenyl acetate hydrolysis (pNPA) to within ~100-fold of the efficiency of human carbonic anhydrase (CA)II and is at least 550-fold better than comparable synthetic complexes. Similarly, CO2 hydration occurs with an efficiency within ~500-fold of CAII. While histidine residues in the absence of Zn(II) exhibit pNPA hydrolysis, miniscule apopeptide activity is observed for CO2 hydration. The kinetic and structural analysis of this first de novo designed hydrolytic metalloenzyme uncovers necessary design features for future metalloenzymes containing one or more metals.
Journal of Inorganic Biochemistry | 2010
Alberta Bergamo; A. Masi; Anna F. A. Peacock; Abraha Habtemariam; Peter J. Sadler; Gianni Sava
We have compared the organometallic arene complexes [(eta(6)-biphenyl)M(ethylenediamine)Cl](+) RM175 (M=Ru(II)) and its isostructural osmium(II) analogue AFAP51 (M=Os(II)) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6x more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231 cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo.
Journal of Medicinal Chemistry | 2008
Hana Kostrhunova; Jakub Florian; Olga Novakova; Anna F. A. Peacock; Peter J. Sadler; Viktor Brabec
This work is the first in-depth study of osmium binding to DNA and confirms the pharmacological activity of a new class of anticancer metallodrugs. We investigated the interactions between the potential biological target DNA and four osmium(II) arene complexes, of the type [(eta 6-arene)Os(LL)Cl]n+, where arene = biphenyl or p-cymene and LL = ethylenediamine, picolinate, or oxinate in an effort to understand their mechanism of action. Most notably we show that these complexes bind to DNA. DNA adducts of the OsII complexes that exhibit promising cytotoxic effects in ovarian tumor cell lines largely distort its conformation. The data are consistent with DNA binding of the complexes containing biphenyl as the arene ligand that involves combined coordination to guanine residues and noncovalent interactions between the arene ligand and DNA. The results also indicate both a mechanism of action and a detoxification mechanism for OsII arene compounds different from those of cisplatin.
Proceedings of the National Academy of Sciences of the United States of America | 2008
Anna F. A. Peacock; Lars Hemmingsen; Vincent L. Pecoraro
Here, we report a previously undescribed approach for controlling metal ion coordination geometry in biomolecules by reorientating amino acid side chains through substitution of L- to D-amino acids. These diastereopeptides allow us to manipulate the spatial orientation of amino acid side chains to alter the sterics of metal binding pockets. We have used this approach to design the de novo metallopeptide, Cd(TRIL12LDL16C)3−, which is an example of Cd(II) bound to 3 L-Cys as exclusively trigonal CdS3, as characterized by a combination of 113Cd NMR and 111mCd PAC spectroscopy. We subsequently show that the physical properties of such a site, such as the high pKa2 for Cd(II) binding of 15.1, is due to the nature of the coordination number and not the ligating group. Further more this approach allowed for the design of a construct, GRANDL12LDL16CL26AL30C, capable of independently binding 2 equivalents of Cd(II) to 2 very similar Cys sites as exclusively 3- and 4-, CdS3 and CdS3O, respectively. Demonstrating that we are capable of controlling the Cd(II) coordination number in these 2 sites solely by varying the nature of a noncoordinating second coordination sphere amino acid, with D-leucine and L-alanine resulting in exclusively 3- and 4-coordinate structures, respectively. Cd(II) was found to selectively bind to the 4-coordinate CdS3O site, demonstrating that a protein can be designed that displays metal-binding selectivity based solely on coordination number control and not on the chemical identity of coordinating ligands.
Current Opinion in Chemical Biology | 2013
Anna F. A. Peacock
The de novo design of artificial metalloproteins from first-principles is a powerful strategy with which to establish the minimum structure required for function, as well as to identify the important design features for tuning the chemistry of the coordinated metal ion. Herein we describe recent contributions to this field, covering metallo-porphyrin, mononuclear and multinuclear metal ion sites engineered into de novo proteins. Using miniature artificial scaffolds these examples demonstrate that complex natural protein folds are not required to mimic naturally occurring metal ion sites in proteins. More importantly progress is being made to engineer de novo metalloproteins capable of performing functions not in the repertoire of biology.
Angewandte Chemie | 2009
Anna F. A. Peacock; Jeanne A. Stuckey; Vincent L. Pecoraro
De novo metallopeptide design contributes significantly to the understanding of protein folding, protein-protein interactions and metal ion sites in biology.[1,2] Within this rubric, work in our research group has been focused on the biochemistry of Cd(II) thiolate sites. A class of peptides based on the parent peptide TRI, Ac-G(LKALEEK)4G-NH2, was designed to assemble in aqueous solution into amphiphilic α-helices. These peptides aggregate to form three stranded coiled coils above pH 5.5.[3] Substitutions can be made to the interior of these coiled coils to generate metal binding sites, potentially with adjacent cavities.[4–7] One benefit of de novo design is that we are no longer limited to the 20 naturally coded amino acids. We demonstrated using two different strategies, that one can achieve a coordinatively unsaturated trigonal planar CdS3 site, by incorporating non-protein amino acids into the peptide sequence. The first approach was to substitute the coordinating L-cysteine (L-Cys) with the bulkier non-protein analogue L-penicillamine (L-Pen), in which the β-methylene protons have been replaced with larger methyl groups.[8] Our second approach was to modify the chirality of the second coordination sphere ligands directly above the metal binding plane (L-Leu → D-Leu), reorienting the Leu side chain towards the C-terminus and the metal binding site. Presumably, this modification sterically inhibits a fourth ligand from binding to the Cd(II).[9,10]
Journal of the American Chemical Society | 2014
Matthew R. Berwick; David J. Lewis; Andrew W. Jones; Rosemary A. Parslow; Timothy R. Dafforn; Helen J. Cooper; John Wilkie; Zoe Pikramenou; Melanie M. Britton; Anna F. A. Peacock
A new peptide sequence (MB1) has been designed which, in the presence of a trivalent lanthanide ion, has been programmed to self-assemble to form a three stranded metallo-coiled coil, Ln(III)(MB1)3. The binding site has been incorporated into the hydrophobic core using natural amino acids, restricting water access to the lanthanide. The resulting terbium coiled coil displays luminescent properties consistent with a lack of first coordination sphere water molecules. Despite this the gadolinium coiled coil, the first to be reported, displays promising magnetic resonance contrast capabilities.
Journal of Inorganic Biochemistry | 2012
Anna F. A. Peacock; Gemma A. Bullen; Lee A. Gethings; Jonathan P. Williams; Frederik H. Kriel; Judy Coates
The coordination of the therapeutically interesting [AuCl(PEt(3))] to the de novo designed peptide, TRIL23C, under aqueous conditions, is reported here. TRIL23C represents an ideal model to investigate the binding of [AuCl(PEt(3))] to small proteins in an effort to develop novel gold(I) phosphine peptide adducts capable of mimicking biological recognition and targeting. This is due to the small size of TRIL23C (30 amino acids), yet stable secondary and tertiary fold, symmetric nature and the availability of only one thiol binding site. [AuCl(PEt(3))] was found to react readily with the Cys side chain in a 1:1 ratio as confirmed by UV-visible, (31)P NMR and mass spectrometry. Circular dichroism confirmed that the coiled coil structure was retained on coordination of the {Au(PEt(3))}(+) unit. Redesign of the exterior of TRIL23C based on a biologically relevant recognition sequence found in GCN4, did not alter the coordination chemistry of [AuCl(PEt(3))]. To the best of our knowledge, this represents the first report on the coordination of gold(I) phosphine compounds to de novo designed peptides, and could lead to the generation of novel gold(I) phosphine peptide therapeutics in the future.
Journal of Physical Chemistry B | 2013
Mark T. Oakley; Emmanuel Oheix; Anna F. A. Peacock; Roy L. Johnston
We present a combined computational and experimental study of the energy landscapes of cyclic tetra-α/β-peptides. We have performed discrete path sampling calculations on a series of cyclic tetra-α/β-peptides to obtain the relative free energies and barriers to interconversion of their conformers. The most stable conformers of cyclo-[(β-Ala-Gly)2] contain all-trans peptide groups. The relative energies of the cis isomers and the cis-trans barriers are lower than in acyclic peptides but not as low as in the highly strained cyclic α-peptides. For cyclic tetra-α/β-peptides containing a single proline residue, of the type cyclo-[β-Ala-Xaa-β-Ala-Pro], the energy landscapes show that the most stable isomers containing cis and trans β-Ala-Pro have similar free energies and are separated by barriers of approximately 15 kcal mol(-1). We show that the underlying energy landscapes of cyclo-[β-Ala-Lys-β-Ala-Pro] and cyclo-[β-Ala-Ala-β-Ala-Pro] are similar, allowing the substitution of the flexible side chain of Lys with Ala to reduce the computational demand of our calculations. However, the steric bulk of the Val side chain in cyclo-[β-Ala-Val-β-Ala-Pro] affects the conformations of the ring, leading to significant differences between its energy landscape and that of cyclo-[β-Ala-Ala-β-Ala-Pro]. We have synthesized the cyclic peptide cyclo-[β-Ala-Lys-β-Ala-Pro], and NMR spectroscopy shows the presence of conformers that interconvert slowly on the NMR time scale at temperatures up to 80 °C. Calculated circular dichroism (CD) spectra for the proposed major isomer of cyclo-[β-Ala-Ala-β-Ala-Pro] are in good agreement with the experimental spectra of cyclo-[β-Ala-Lys-β-Ala-Pro], suggesting that the Ala cyclic tetrapeptide is a viable model for the Lys analogue.