Publications by authors named "Anna F A Peacock"

Oligoarginine cell-penetrating peptides (CPPs) are short peptides that can enhance drug delivery into cells and are of particular interest in ocular topical formulations for age-related macular degeneration (AMD) treatments. The length and structural characteristics of these peptides are considered crucial for drug delivery. This study investigates how oligoarginine length (R) affects their penetration mechanism, drug delivery capabilities, and antimicrobial properties, providing insights into their potential roles in AMD treatment delivery.

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We report the preparation and spectroscopic characterization of a highly elusive copper site bound exclusively to oxygen donor atoms within a protein scaffold. Despite copper generally being considered unsuitable for use in MRI contrast agents, which in the clinic are largely Gd(III) based, the designed copper coiled coil displays relaxivity values equal to, or superior than, those of the Gd(III) analog at clinical field strengths. The creation of this new-to-biology proteinaceous CuO-binding site demonstrates the power of the de novo peptide design approach to access chemistry for abiological applications, such as for the development of MRI contrast agents.

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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.

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Herein we report unprecedented location-dependent, size-selective binding to designed lanthanide (Ln ) sites within miniature protein coiled coil scaffolds. Not only do these engineered sites display unusual Ln selectivity for moderately large Ln ions (Nd to Tb), for the first time we demonstrate that selectivity can be location-dependent and can be programmed into the sequence. A 1 nm linear translation of the binding site towards the N-terminus can convert a selective site into a highly promiscuous one.

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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.

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Aim: The development of a polyarginine cell-penetrating peptide (CPP) could enable the treatment of age-related macular degeneration, with drugs like bevacizumab, to be administered using eye drops instead of intravitreal injections. Topical formulations have a vast potential impact on healthcare by increasing patient compliance while reducing the financial burden. However, as the ocular preparations may contain several doses, it is essential to understand the stability of the bevacizumab+CPP conjugate produced.

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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.

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Despite increased sterilisation and education campaigns, hospital acquired infections have not been eradicated. Bacterial colonisation of frequent touch surfaces is key in the transmission of infection. Most current technologies cannot provide a material which can rapidly kill bacteria.

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The reversible photocontrol of an enzyme governing blood coagulation is demonstrated. The thrombin binding aptamer (TBA), was rendered photochromic by modification with two anthracene groups. Light-triggered anthracene photodimerisation distorts its structure, inhibiting binding of the enzyme thrombin, which in turn triggers catalysis and the resulting clotting process.

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Here, we report how the stability of polyion complex (PIC) particles containing 's elastase (LasB) degradable peptides and antimicrobial poly(ethylene imine) is significantly improved by careful design of the peptide component. Three LasB-degradable peptides are reported herein, all of them carrying the LasB-degradable sequence -GLA- and for which the number of anionic amino acids and cysteine units per peptide were systematically varied. Our results suggest that while net charge and potential to cross-link via disulfide bond formation do not have a predictable effect on the ability of LasB to degrade these peptides, a significant effect of these two parameters on particle preparation and stability is observed.

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Herein the first example of a bimetallic coiled coil featuring a lanthanide binding site is reported, opening opportunities to exploit the attractive NMR and photophysical properties of the lanthanides in multi metallo protein design. In our efforts to fully characterise the system we identified for the first time that lanthanide binding to such sites is pH dependent, with optimal binding at neutral pH, and that the double AsnAsp site is more versatile in this regard than the single Asp site. Our second site featured the structural HgCys site, the chemistry of which was essentially unaltered by the presence of the lanthanide site.

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Here, we describe the preparation and characterisation of polyion complex (PIC) nanoparticles containing last resort antimicrobial polymyxin B (Pol-B). PIC nanoparticles were prepared with poly(styrene sulphonate) (PSS) as an inert component, across a range of degrees of polymerisation to evaluate the effect that multivalency of this electrolyte has on the stability and antimicrobial activity of these nanoparticles. Our results demonstrate that while nanoparticles prepared with longer polyelectrolytes are more stable under simulated physiological conditions, those prepared with shorter polyelectrolytes have a higher antimicrobial activity.

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Purpose: To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection.

Methods: CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA.

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Although metal ion binding to naturally occurring l-amino acid proteins is well documented, understanding the impact of the opposite chirality (d-)amino acids on the structure and stereochemistry of metals is in its infancy. We examine the effect of a d-configuration cysteine within a designed l-amino acid three-stranded coiled coil in order to enforce a precise coordination number on a metal center. The d chirality does not alter the native fold, but the side-chain re-orientation modifies the sterics of the metal binding pocket.

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Article Synopsis
  • - The study focuses on creating polyion complex (PIC) particles for delivering Polymyxin B (Pol-B), an antibiotic used against hard-to-treat gram-negative bacteria.
  • - Researchers identified various conditions to efficiently combine Pol-B with poly(styrene sulphonate) (PSS) to produce stable colloidal PIC particles with different ratios of Pol-B to PSS.
  • - The stability of these PIC particles was tested in conditions similar to those found in the human body, and their antimicrobial effects against a specific gram-negative bacterium were preliminarily evaluated.
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The interface between implanted devices and their host tissue is complex and is often optimized for maximal integration and cell adhesion. However, this also gives a surface suitable for bacterial colonization. We have developed a novel method of modifying the surface at the material-tissue interface with an antimicrobial peptide (AMP) coating to allow cell attachment while inhibiting bacterial colonization.

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Here we present new enzyme-responsive polyion complex (PIC) nanoparticles prepared from antimicrobial poly(ethylene imine) and an anionic enzyme-responsive peptide targeting 's elastase. The synthetic conditions used to prepare these nanomaterials allowed us to optimise particle size and charge, and their stability under physiological conditions. We demonstrate that these enzyme responsive PIC nanoparticles are selectively degraded in the presence of elastase without being affected by other endogenous elastases.

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Herein, we establish for the first time the design principles for lanthanide coordination within coiled coils, and the important consequences of binding site translation. By interrogating design requirements and by systematically translating binding site residues, one can influence coiled coil stability and more importantly, the lanthanide coordination chemistry. A 10 Å binding site translation along a coiled coil, transforms a coordinatively saturated Tb(Asp)(Asn) site into one in which three exogenous water molecules are coordinated, and in which the Asn layer is no longer essential for binding, Tb(Asp)(HO).

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Bioinorganic chemists aspire to achieve the same exquisite and highly controlled inorganic chemistry featured in biology. An exciting mimetic approach involves the use of miniature artificial protein scaffolds designed de novo (often based on the coiled coil (CC) scaffold), for reproducing native metal ion sites and their function. Recently, there is increased interest, instead, in the design of xeno-metal sites within CC assemblies.

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The ability to discriminate between epigenetic variants in DNA is a necessary tool if we are to increase our understanding of the roles that they play in various biological processes and medical conditions. Herein, it is demonstrated how a simple two-step fluorescent probe assay can be used to differentiate all three major epigenetic variants of cytosine at a single locus site in a target strand of DNA.

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Current processes for coating titanium implants with ceramics involve very high energy techniques with associated high cost and disadvantages such as heterogeneity of the coatings, phase transformations and inability to coat complex structures. In order to address the above problems, we propose a biomimetic hydroxyapatite coating process with the use of peptides that can bind both on titanium surfaces and hydroxyapatite. The peptides enabled homogeneous coating of a titanium surface with hydroxyapatite.

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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.

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This chapter describes how de novo designed peptides can be used as novel preorganized ligands for metal ion coordination. The focus is on the design of peptides which are programmed to spontaneously self-assemble into α-helical coiled coils in aqueous solution, and how metal ion binding sites can be engineered onto and into these structures. In addition to describing the various design principles, some key examples are covered illustrating the success of this approach, including a more detailed example in the case study.

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