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.
Special agents: Organometallic complexes show increasing promise as therapeutic and diagnostic agents. This Focus Review describes some successes in the field, focusing in particular on ruthenium and osmium arene complexes as potential anticancer agents.
Cryptococcosis is a potentially lethal fungal infection of humans caused by organisms within the Cryptococcus neoformans/gattii species complex. Whilst C. neoformans is a relatively common pathogen ...of immunocompromised individuals, C. gattii is capable of acting as a primary pathogen of immunocompetent individuals. Within the host, both species undergo morphogenesis to form titan cells: exceptionally large cells that are critical for disease establishment. To date, the induction, defining attributes, and underlying mechanism of titanisation have been mainly characterized in C. neoformans. Here, we report the serendipitous discovery of a simple and robust protocol for in vitro induction of titan cells in C. gattii. Using this in vitro approach, we reveal a remarkably high capacity for titanisation within C. gattii, especially in strains associated with the Pacific Northwest Outbreak, and characterise strain-specific differences within the clade. In particular, this approach demonstrates for the first time that cell size changes, DNA amplification, and budding are not always synchronous during titanisation. Interestingly, however, exhibition of these cell cycle phenotypes was correlated with genes associated with cell cycle progression including CDC11, CLN1, BUB2, and MCM6. Finally, our findings reveal exogenous p-Aminobenzoic acid to be a key inducer of titanisation in this organism. Consequently, this approach offers significant opportunities for future exploration of the underlying mechanism of titanisation in this genus.
Incorporating metals into de novo proteins Peacock, Anna FA
Current opinion in chemical biology,
December 2013, 2013-Dec, 2013-12-00, 20131201, Letnik:
17, Številka:
6
Journal Article
Recenzirano
Odprti dostop
•Recent advances in the design of metal ion sites within de novo protein scaffolds are described.•Miniature protein scaffolds are capable of tuning metal ion properties.•Functionality not performed ...by biology can also be achieved using this approach.
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.
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 (pNPA) hydrolysis with an efficiency only ~100-fold less than that of human carbonic anhydrase (CA)II and at least 550-fold better than comparable synthetic complexes. Similarly, CO(2) hydration occurs with an efficiency within ~500-fold of CAII. Although histidine residues in the absence of Zn(II) exhibit pNPA hydrolysis, miniscule apopeptide activity is observed for CO(2) hydration. The kinetic and structural analysis of this first de novo designed hydrolytic metalloenzyme reveals necessary design features for future metalloenzymes containing one or more metals.
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•We report the preparation of PIC particles loaded with clinically relevant antibiotic Polymyxin B.•PIC particle formulation is optimised to accommodate different loadings of ...Polymyxin B.•PIC particles inhibit the growth of Pseudomonas aeruginosa in a particle dependent manner.
Here, we describe novel polyion complex (PIC) particles for the delivery of Polymyxin B (Pol-B), an antimicrobial peptide currently used in the clinic as a last resort antibiotic against multidrug-resistant gram-negative bacteria. A range of conditions for the controlled assembly of Pol-B with poly(styrene sulphonate) (PSS) has been identified which let us prepare stable colloidal PIC particles. This way, PIC particles containing different Pol-B:PSS ratios have been prepared and their stability under simulated physiological conditions (i.e. pH, osmotic pressure and temperature) characterised. Furthermore, preliminary evaluation of the antimicrobial activity of these Pol-B containing PIC particles has been performed, by monitoring their effect on the growth of Pseudomonas aeruginosa, an opportunistic gram-negative bacterium.
The OsII arene ethylenediamine (en) complexes (η6-biphenyl)Os(en)ClZ, Z = BPh4 (4) and BF4 (5), are inactive toward A2780 ovarian cancer cells despite 4 being isostructural with an active RuII ...analogue, 4R. Hydrolysis of 5 occurred 40 times more slowly than 4R. The aqua adduct 5A has a low pK a (6.3) compared to that of (η6-biphenyl)Ru(en)(OH2)2+ (7.7) and is therefore largely in the hydroxo form at physiological pH. The rate and extent of reaction of 5 with 9-ethylguanine were also less than those of 4R. We replaced the neutral en ligand by anionic acetylacetonate (acac). The complexes (η6-arene)Os(acac)Cl, arene = biphenyl (6), benzene (7), and p-cymene (8), adopt piano-stool structures similar to those of the RuII analogues and form weak dimers through intermolecular (arene)CH···O(acac) H-bonds. Remarkably, these OsII acac complexes undergo rapid hydrolysis to produce not only the aqua adduct, (η6-arene)Os(acac)(OH2)+, but also the hydroxo-bridged dimer, (η6-arene)Os(μ2-OH)3Os(η6-arene)+. The pK a values for the aqua adducts 6A, 7A, and 8A (7.1, 7.3, and 7.6, respectively) are lower than that for (η6-p-cymene)Ru(acac)(OH2)+ (9.4). Complex 8A rapidly forms adducts with 9-ethylguanine and adenosine, but not with cytidine or thymidine. Despite their reactivity toward nucleobases, complexes 6−8 were inactive toward A549 lung cancer cells. This is attributable to rapid hydrolysis and formation of unreactive hydroxo-bridged dimers which, surprisingly, were the only species present in aqueous solution at biologically relevant concentrations. Hence, the choice of chelating ligand in OsII (and RuII) arene complexes can have a dramatic effect on hydrolysis behavior and nucleobase binding and provides a means of tuning the reactivity and the potential for discovery of anticancer complexes.
For much of their history, lanthanides were thought to be biologically inert. However, the last decade has seen the discovery and development of the field of native lanthanide biochemistry. ...Lanthanides exhibit a variety of interesting photophysical properties from which many useful applications derive. The development of effective functional lanthanide complexes requires control of their coordination sphere; something proteins manage very effectively through their 3D metal-binding sites. α-Helical coiled coil peptides are miniature scaffolds which can be designed de novo and can retain the favourable properties of larger proteins within a much simplified system. Metal binding sites, including those which bind lanthanides can be engineered into the coiled coil sequence. This review will highlight the opportunities presented by the use of coiled coil peptides as scaffolds for lanthanide binding and the potential to control the coordination environment by simple modifications to peptide sequence. Designed lanthanide coiled coils offer opportunities to gain greater insight into native lanthanide biochemistry as well as to develop new functional complexes, including imaging agents.
The unprecedented use of anthracene photodimerization within a protein or peptide system is explored through its incorporation into a DNA-binding peptide, derived from the GCN4 transcription factor. ...This study demonstrates an effective and dynamic interplay between a photoreaction and a peptide-DNA assembly, with each process able to exert control over the other.
The metal hydration state within a designed coiled coil can be progressively tuned across the full integer range (3 → 0 aqua ligands), by careful choice of a second sphere terminal residue, including ...the lesser used Trp. Potential implications include a four-fold change in MRI relaxivity when applied to lanthanide coiled coils.
The hydration state of designed metal binding sites in coiled coils can be tuned by terminal second sphere residues.
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