Gene/Protein Disease Symptom Drug Enzyme Compound
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This report highlights the advantages of low-affinity, multivalent interactions to recognize one cell type over another. Our goal was to devise a strategy to mediate selective killing of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. To test whether multivalent interactions could lead to highly specific cell targeting, we used a chemically synthesized small-molecule ligand composed of two distinct motifs: (1) an Arg-Gly-Asp (RGD) peptidomimetic that binds tightly (Kd approximately 10(-9)M) to alphavbeta3 integrins and (2) the galactosyl-alpha(1-3)galactose (alpha-Gal epitope), which is recognized by human anti-alpha-galactosyl antibodies (anti-Gal). Importantly, anti-Gal binding requires a multivalent presentation of carbohydrate residues; anti-Gal antibodies interact weakly with the monovalent oligosaccharide (Kd approximately 10(-5)M) but bind tightly (Kd approximately 10(-11) M) to multivalent displays of alpha-Gal epitopes. Such a display is generated when the bifunctional conjugate decorates a cell possessing a high level of alphavbeta3 integrin; the resulting cell surface, which presents many alpha-Gal epitopes, can recruit anti-Gal, thereby triggering complement-mediated lysis. Only those cells with high levels of the integrin receptor are killed. In contrast, doxorubicin tethered to the RGD-based ligand affords indiscriminate cell death. These results highlight the advantages of exploiting the type of the multivalent recognition processes used by physiological systems to discriminate between cells. The selectivity of this strategy is superior to traditional, abiotic, high-affinity targeting methods. Our results have implications for the treatment of cancer and other diseases characterized by the presence of deleterious cells.
ACS Chem Biol 2007 Feb 20
PMID:Selective tumor cell targeting using low-affinity, multivalent interactions. 1729 Oct 50

Herein we report the spontaneous reduction of silver ions into nanostructures by yeast surface-displayed glutamic acid (E(6)) and aspartic acid (D(6)) peptides. Light spectroscopy and electron microscopy reveal that silver ions are photoreduced in the presence of the polycarboxylic acid-containing peptides and ambient light, with an increase in reduction capability of E(6) expressing yeast over D(6) yeast. The importance of tethering peptides to a biological scaffold was inferred by observing the reduced particle forming capacity of soluble peptides with respect to corresponding yeast-displayed peptides. This principle was further extended to the M13 virus for fabrication of crystalline silver nanowires. These insights into the spontaneous reduction of metal ions on biological scaffolds should help further the formation of novel nanomaterials in biological systems.
ACS Nano 2008 Jul
PMID:Peptide-mediated reduction of silver ions on engineered biological scaffolds. 1920 18

This paper describes the synthesis of single-crystalline Ag nanoplates using the extract of unicellular green alga Chlorella vulgaris at room temperature. Proteins in the extract were involved in the biological synthesis, providing the dual function of Ag ion reduction and shape-controlled synthesis of nanosilver. Hydroxyl groups in Tyr residues and carboxyl groups in Asp and/or Glu residues were further identified as the most active functional groups for Ag ion reduction and for directing the anisotropic growth of Ag nanoplates, respectively. The kinetics of Ag ion reduction in biological systems was discussed and probed by using custom-designed peptides. The results showed the Tyr content (the reduction source) and the content of Ag complexers (the reaction inhibitors, e.g., His and Cys) in the protein molecules as important factors affecting the reduction kinetics. The comprehensive system identification effort has led to the design of a simple bifunctional tripeptide (DDY-OMe) with one Tyr residue as the reduction source and two carboxyl groups in the Asp residues as shape-directors, which could produce small Ag nanoplates with low polydispersivity in good yield (>55%). The roles of the carboxyl groups in the formation of Ag nanoplates were also discussed.
ACS Nano 2007 Dec
PMID:Silver nanoplates: from biological to biomimetic synthesis. 1920 64

We investigated the role of beta(1) integrin in mammalian fertilization and the mode of inhibition of fertilinbeta-derived polymers. We determined that polymers displaying the Glu-Cys-Asp peptide from the fertilinbeta disintegrin domain mediate inhibition of mammalian fertilization through a beta(1) integrin receptor on the egg surface. Inhibition of fertilization is a consequence of competition with sperm binding to the cell surface, not activation of an egg-signaling pathway. The presence of the beta(1) integrin on the egg surface increases the rate of sperm attachment but does not alter the total number of sperm that can attach or fuse to the egg. We conclude that the presence of beta(1) integrin enhances the initial adhesion of sperm to the egg plasma membrane and that subsequent attachment and fusion are mediated by additional egg and sperm proteins present in the beta(1) integrin complex. Therefore, the mechanisms by which sperm fertilize wild-type and beta(1) knockout eggs are different.
ACS Chem Biol 2009 May 15
PMID:Beta1 integrin is an adhesion protein for sperm binding to eggs. 1944 61

We previously demonstrated that the supramolecular self-assembly of cyanines could be useful for developing fluorescent enzymatic assays. We took that concept a step further by synthesizing a covalent adduct of the tetrapeptide Asp-Glu-Val-Asp (DEVD) and a cyanine (DEVD-cyanine). The DEVD-cyanine due to its canonical sequence was recognized and hydrolyzed by the proteases, Caspase-3 and -7 in 96- or 384-microwell plate reactions. The catalytically liberated cyanine self-assembled upon scaffolds of carboxymethylamylose (CMA), carboxymethylcellulose (CMC), or a mixture of CMA and CMC resulting in a J aggregate exhibiting bright fluorescence at a 470 nm emission wavelength (optimum signal/background using excitation wavelengths of 415-440 nm). The fluorescence intensity increased with enzyme and substrate concentrations or reaction time and exhibited classical saturation profiles of a rectangular hyperbola. Saturation of the reaction was at 30 U/mL (1 microg/mL) Caspase-3 and 250 microM DEVD-cyanine. The reaction kinetics was linear between 1 and 20 min and saturated at 60 min. The affinity constant (Km) for DEVD-cyanine was approximately 23 microM, similar to those of previously reported values for other DEVD substrates of Caspase-3. Maximal fluorescence emission was observed by using a mixture of CMA and CMC scaffolds at 65 and 35 microM, respectively. The reaction kinetics of Caspase-7 executed in a 384-well plate was similar to the reaction kinetics of Caspase-3 conducted in a 96-well plate. We believe that this is the first demonstration of a cyanine liberated from a covalent adduct due to protease action, leading to supramolecular self-assembly and the detection of protease activity.
ACS Appl Mater Interfaces 2009 Jan
PMID:New high-throughput screening protease assay based upon supramolecular self-assembly. 2035 68

A two-step, high-purity, high-yield synthesis of nanoparticulate vanadium dioxide, which has a greater than 10-fold potential cost reduction is reported. This consists of a short reflux of V2O5 with aspartic acid, followed by calcination at 600 degrees C or above. The particles produced have a mean diameter of approximately 90 nm with phase change characteristics of transition temperature and enthalpy that compare favorably with a commercial standard. In cases where the reduction reaction has progressed too far and a mixture of vanadium(III) and -(IV) is formed, redispersion and aging of the particulate product in water preferentially oxidizes the vanadium(III) component to vanadium(IV), thus allowing a versatile route to achieving a high-purity material. The synthesis was also used to deposit high-purity phases of VO2 onto the surfaces of other particles, and significant differences in the structural phase transition behavior and even the crystal structure were found for deposited samples. The data suggest that substrate properties may affect the characteristics of the structural phase transition, and this has significant implications for measurements on, and applications of, deposited VO2 layers and films.
ACS Appl Mater Interfaces 2009 Sep
PMID:Production of VO2 M1 and M2 nanoparticles and composites and the influence of the substrate on the structural phase transition. 2035 12

To make polycaprolactone (PCL) more suitable for tissue engineering, PCL in the form of electrospun fibrous scaffolds was first modified with 1,6-hexamethylenediamine to introduce amino groups on their surface. Various biomolecules, i.e., collagen, chitosan, and Gly-Arg-Gly-Asp-Ser (GRGDS) peptide, were then immobilized on their surface, with N,N'-disuccinimidylcarbonate being used as the coupling agent. Dynamic water contact angle measurement indicated that the scaffold surface became more hydrophilic after the aminolytic treatment and the subsequent immobilization of the biomolecules. The appropriateness of these PCL fibrous scaffolds for the tissue/cell culture was evaluated in vitro with three different cell lines, e.g., mouse fibroblasts (L929), human epidermal keratinocytes (HEK001), and mouse calvaria-derived preosteoblastic cells (MC3T3-E1). Both the neat and the modified PCL fibrous scaffolds released no substances in the levels that were harmful to these cells. Among the various biomolecule-immobilized PCL fibrous scaffolds, the ones that had been immobilized with type I collagen, a Arg-Gly-Asp-containing protein, showed the greatest ability to support both the attachment and the proliferation of all of the investigated cell types, followed by those that had been immobilized with GRGDS peptide.
ACS Appl Mater Interfaces 2009 May
PMID:Immobilization of biomolecules on the surface of electrospun polycaprolactone fibrous scaffolds for tissue engineering. 2035 94

In this paper, the alpha-beta cyclodextrin dimer is designed via "click" chemistry to connect the hydrophilic and hydrophobic segments to form self-assembled noncovalently connected micelles (NCCMs) through host-guest interactions. A peptide containing the Arg-Gly-Asp (RGD) sequence was introduced to NCCMs as a target ligand to improve the cell uptake efficacy, while PEGylated technology was employed via benzoic-imine bonds to protect the ligands in normal tissues and body fluid. In addition, two fluorescent dyes were conjugated to different segments to track the formation of the micelles as well as the assemblies. It was found that the targeting property of NCCMs was switched off before reaching the tumor sites and switched on after removing the poly(ethylene glycol) (PEG) segment in the tumor sites, which was called "tumor-triggered targeting". With deshielding of the PEG segment, the drugs loaded in NCCMs could be released rapidly due to the thermoinduced phase transition. The new concept of "tumor-triggered targeting" proposed here has great potential for cancer treatment.
ACS Nano 2010 Jul 27
PMID:Core-shell nanosized assemblies mediated by the alpha-beta cyclodextrin dimer with a tumor-triggered targeting property. 2052 28

A biocompatible hydrogel self-assembled from a peptide comprised of a peptide backbone containing Arg-Gly-Asp (RGD) sequence and a hydrophobic N-fluorenyl-9-methoxycarbonyl (FMOC) tail was designed and prepared to load antiproliferative model drug (5-fluorouracil, 5-Fu). After administering this 5-Fu-loaded peptide hydrogel in the filtering surgery of rabbit eyes, because of the sustained release of 5-Fu from the hydrogel to inhibit the scleral flap fibrosis efficiently, the pathology and immunohistochemistry demonstrate that the filtration fistula is patent without postoperative scarring formation, resulting in the significantly low intraocular pressure (IOP) of the rabbit eyes within postoperative 28 days. In a comparison with the conventional 5-Fu exposure, the strategy demonstrated here presents several advantages including providing convenience and preventing the toxicity of 5-Fu to the surrounding ocular tissues efficiently, suggesting a feasibility of this peptide hydrogel as a potential implanted drug delivery system for the inhibition of postoperative scarring formation.
ACS Appl Mater Interfaces 2010 Sep
PMID:Peptide hydrogel as an intraocular drug delivery system for inhibition of postoperative scarring formation. 2070 34

The creation of synthetic enzymes with predefined functions represents a major challenge in future synthetic biology applications. Here, we describe six structures of de novo proteins that have been determined using protein crystallography to address how simple enzymes perform catalysis. Three structures are of a protein, DX, selected for its stability and ability to tightly bind ATP. Despite the addition of ATP to the crystallization conditions, the presence of a bound but distorted ATP was found only under excess ATP conditions, with ADP being present under equimolar conditions or when crystallized for a prolonged period of time. A bound ADP cofactor was evident when Asp was substituted for Val at residue 65, but ATP in a linear configuration is present when Phe was substituted for Tyr at residue 43. These new structures complement previously determined structures of DX and the protein with the Phe 43 to Tyr substitution [Simmons, C. R., et al. (2009) ACS Chem. Biol. 4, 649-658] and together demonstrate the multiple ADP/ATP binding modes from which a model emerges in which the DX protein binds ATP in a configuration that represents a transitional state for the catalysis of ATP to ADP through a slow, metal-free reaction capable of multiple turnovers. This unusual observation suggests that design-free methods can be used to generate novel protein scaffolds that are tailor-made for catalysis.
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PMID:Three-dimensional structures reveal multiple ADP/ATP binding modes for a synthetic class of artificial proteins. 2082 7


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