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Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site.
Karuturi R, Al-Horani RA, Mehta SC, Gailani D, Desai UR
(2013) J Med Chem 56: 2415-28
MeSH Terms: Allosteric Regulation, Biomimetic Materials, Catalytic Domain, Drug Discovery, Factor XIa, Glycosaminoglycans, Heparin, Humans, Hydrophobic and Hydrophilic Interactions, Protease Inhibitors, Quinazolinones, Sulfates
Show Abstract · Added May 19, 2014
To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the Vmax of substrate hydrolysis without influencing the KM. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.
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12 MeSH Terms
Application of multianalyte microphysiometry to characterize macrophage metabolic responses to oxidized LDL and effects of an apoA-1 mimetic.
Kimmel DW, Dole WP, Cliffel DE
(2013) Biochem Biophys Res Commun 431: 181-5
MeSH Terms: Animals, Apolipoprotein A-I, Atherosclerosis, Biomimetic Materials, Cell Line, Glucose, Lactic Acid, Lipoproteins, LDL, Macrophages, Mice, Oxygen, Peptides, Potentiometry
Show Abstract · Added January 20, 2015
Although the interaction of macrophages with oxidized low density liopoprotein (oxLDL) is critical to the pathogenesis of atherosclerosis, relatively little is known about their metabolic response to oxLDL. Our development of the multianalyte microphysiometer (MAMP) allows for simultaneous measurement of extracellular metabolic substrates and products in real-time. Here, we use the MAMP to study changes in the metabolic rates of RAW-264.7 cells undergoing respiratory burst in response to oxLDL. These studies indicate that short duration exposure of macrophages to oxLDL results in time-dependent increases in glucose and oxygen consumption and in lactate production and extracellular acidification rate. Since apolipoprotein A-I (apoA-I) and apoA-I mimetics prevent experimental atherosclerosis, we hypothesized that the metabolic response of the macrophage during respiratory burst can be modulated by apoA-I mimetics. We tested this hypothesis by examining the effects of the apoA-I peptide mimetic, L-4F, alone and complexed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) on the macrophage metabolic response to oxLDL. L-4F and the DMPC/L-4F complexes attenuated the macrophage respiratory burst in response to oxLDL. The MAMP provides a novel approach for studying macrophage ligand-receptor interactions and cellular metabolism and our results provide new insights into the metabolic effects of oxLDL and mechanism of action of apoA-I mimetics.
Copyright © 2013 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Biomimetic monolayer-protected gold nanoparticles for immunorecognition.
Harkness KM, Turner BN, Agrawal AC, Zhang Y, McLean JA, Cliffel DE
(2012) Nanoscale 4: 3843-51
MeSH Terms: Animals, Antibodies, Antigens, Biomimetic Materials, Epitopes, Gold, Metal Nanoparticles, Mice, Peptides, Tissue Distribution
Show Abstract · Added January 20, 2015
Gold nanoparticles (AuNPs) protected by self-assembled monolayers (SAMs) are capable of presenting precisely engineered surfaces at the nanoscale, allowing the mimicry of biomacromolecules on an artificial platform. Here we review the generation, characterization, and applications of monolayer-protected AuNPs that have been designed for immunorecognition by the integration of an oligopeptide epitope into the protecting monolayer. The resulting peptide-AuNP conjugate is an effective platform for biomimesis, as demonstrated by multiple studies. Recent work is presented and future directions for this field of research are discussed.
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10 MeSH Terms
Biomarker-mediated disruption of coffee-ring formation as a low resource diagnostic indicator.
Trantum JR, Wright DW, Haselton FR
(2012) Langmuir 28: 2187-93
MeSH Terms: Antigens, Protozoan, Biomarkers, Biomimetic Materials, Clinical Chemistry Tests, Fluorescent Dyes, Histidine, Limit of Detection, Magnets, Malaria, Microfluidic Analytical Techniques, Nanoparticles, Protozoan Proteins, Volatilization
Show Abstract · Added May 27, 2014
The ring pattern resulting from the unique microfluidics in an evaporating coffee drop is a well-studied mass transport phenomenon generating interest in the research community mostly from a mechanistic perspective. In this report, we describe how biomarker-induced particle-particle assemblies, magnetic separation, and evaporation-driven ring formation can be combined for simple pathogen detection. In this assay design, the presence of biomarkers causes self-assembly of a magnetic nanoparticle and a fluorescently labeled micrometer-sized particle. A small spherical magnet under the center of the drop prevents these assemblies from migrating to the drop's edge while a nonreactive control particle flows to the edge forming a ring pattern. Thus the presence or absence of biomarker results in distinctly different distributions of particles in the dried drop. Proof-of-principle studies using poly-L-histidine, a peptide mimic of the malaria biomarker pfHRPII, show that the predicted particle distributions occur with a limit of detection of approximately 200-300 nM.
© 2011 American Chemical Society
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13 MeSH Terms
Nanoparticle-based biologic mimetics.
Cliffel DE, Turner BN, Huffman BJ
(2009) Wiley Interdiscip Rev Nanomed Nanobiotechnol 1: 47-59
MeSH Terms: Biomimetic Materials, Biomimetics, Biosensing Techniques, Equipment Design, Nanoparticles, Nanotechnology
Show Abstract · Added January 20, 2015
Centered on solid chemistry foundations, biology and materials science have reached a crossroad where bottom-up designs of new biologically important nanomaterials are a reality. The topics discussed here present the interdisciplinary field of creating biological mimics. Specifically, this discussion focuses on mimics that are developed using various types of metal nanoparticles (particularly gold) through facile synthetic methods. These methods conjugate biologically relevant molecules, e.g., small molecules, peptides, proteins, and carbohydrates, in conformationally favorable orientations on the particle surface. These new products provide stable, safe, and effective substitutes for working with potentially hazardous biologicals for applications such as drug targeting, immunological studies, biosensor development, and biocatalysis. Many standard bioanalytical techniques can be used to characterize and validate the efficacy of these new materials, including quartz crystal microbalance (QCM), surface plasmon resonance (SPR), and enzyme-linked immunosorbent assay (ELISA). Metal nanoparticle-based biomimetics continue to be developed as potential replacements for the native biomolecule in applications of immunoassays and catalysis.
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6 MeSH Terms
Computational predictions of the tensile properties of electrospun fibre meshes: effect of fibre diameter and fibre orientation.
Stylianopoulos T, Bashur CA, Goldstein AS, Guelcher SA, Barocas VH
(2008) J Mech Behav Biomed Mater 1: 326-35
MeSH Terms: Biomimetic Materials, Computer Simulation, Electrochemistry, Extracellular Matrix, Fibrillar Collagens, Models, Chemical, Molecular Conformation, Particle Size, Polyurethanes, Rotation, Tensile Strength
Show Abstract · Added February 23, 2016
The mechanical properties of biomaterial scaffolds are crucial for their efficacy in tissue engineering and regenerative medicine. At the microscopic scale, the scaffold must be sufficiently rigid to support cell adhesion, spreading, and normal extracellular matrix deposition. Concurrently, at the macroscopic scale the scaffold must have mechanical properties that closely match those of the target tissue. The achievement of both goals may be possible by careful control of the scaffold architecture. Recently, electrospinning has emerged as an attractive means to form fused fibre scaffolds for tissue engineering. The diameter and relative orientation of fibres affect cell behaviour, but their impact on the tensile properties of the scaffolds has not been rigorously characterized. To examine the structure-property relationship, electrospun meshes were made from a polyurethane elastomer with different fibre diameters and orientations and mechanically tested to determine the dependence of the elastic modulus on the mesh architecture. Concurrently, a multiscale modelling strategy developed for type I collagen networks was employed to predict the mechanical behaviour of the polyurethane meshes. Experimentally, the measured elastic modulus of the meshes varied from 0.56 to 3.0 MPa depending on fibre diameter and the degree of fibre alignment. Model predictions for tensile loading parallel to fibre orientation agreed well with experimental measurements for a wide range of conditions when a fitted fibre modulus of 18 MPa was used. Although the model predictions were less accurate in transverse loading of anisotropic samples, these results indicate that computational modelling can assist in design of electrospun artificial tissue scaffolds.
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11 MeSH Terms
Biomimetic glycoliposomes as nanocarriers for targeting P-selectin on activated platelets.
Zhu J, Xue J, Guo Z, Zhang L, Marchant RE
(2007) Bioconjug Chem 18: 1366-9
MeSH Terms: Animals, Binding Sites, Biomimetic Materials, Drug Delivery Systems, Glycolipids, Humans, Hydrophobic and Hydrophilic Interactions, Leukocytes, Lewis Blood Group Antigens, Liposomes, Membrane Glycoproteins, Microscopy, Fluorescence, Nanoparticles, Oligosaccharides, Platelet Activation, Polyethylene Glycols, Vascular Diseases
Show Abstract · Added December 8, 2015
The cell glycocalyx is an attractive model for surface modification of liposomes with the objectives of tissue targeting and prolonged circulation time. Here, we reported on glycocalyx-mimicking liposomes, prepared by incorporating a glycolipid of 3'-sulfo-Lewis a (SuLe(a))-PEG-DSPE with a headgroup of SuLe(a) and a spacer of poly(ethylene glycol) (PEG) linked to two hydrophobic tails. This PEG spaced structure is used to mimic the extended structure of P-selectin glycoprotein ligand 1 (PSGL-1) on activated leukocytes, in order to facilitate the specific binding of liposomes to the receptor of P-selectin expressed on activated platelets. Our results indicate that SuLe(a)-PEG-DSPE can form stable, narrowly distributed liposomes with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol, with a vesicle size of 113.3 nm. The resultant SuLe(a)-PEG-liposomes can facilitate their binding to the receptor of P-selectin 22 times higher than SuLe(a)-liposomes without a PEG spacer. Further studies by fluorescence microscopy show that SuLe(a)-PEG-liposomes can bind to activated platelets in vitro effectively. It suggests that biomimetic SuLe(a)-PEG-liposomes may be used as nanocarriers to target activated platelets for drug delivery to the injury sites of cardiovascular diseases.
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17 MeSH Terms
Assessing laser-tissue damage with bioluminescent imaging.
Wilmink GJ, Opalenik SR, Beckham JT, Davidson JM, Jansen ED
(2006) J Biomed Opt 11: 041114
MeSH Terms: Animals, Biomimetic Materials, Cells, Cultured, Dose-Response Relationship, Radiation, HSP70 Heat-Shock Proteins, Humans, Lasers, Luminescent Measurements, Mice, Microscopy, Fluorescence, Radiation Dosage, Risk Assessment, Risk Factors, Skin, Skin, Artificial
Show Abstract · Added December 10, 2013
Effective medical laser procedures are achieved by selecting laser parameters that minimize undesirable tissue damage. Traditionally, human subjects, animal models, and monolayer cell cultures have been used to study wound healing, tissue damage, and cellular effects of laser radiation. Each of these models has significant limitations, and consequently, a novel skin model is needed. To this end, a highly reproducible human skin model that enables noninvasive and longitudinal studies of gene expression was sought. In this study, we present an organotypic raft model (engineered skin) used in combination with bioluminescent imaging (BLI) techniques. The efficacy of the raft model was validated and characterized by investigating the role of heat shock protein 70 (hsp70) as a sensitive marker of thermal damage. The raft model consists of human cells incorporated into an extracellular matrix. The raft cultures were transfected with an adenovirus containing a murine hsp70 promoter driving transcription of luciferase. The model enables quantitative analysis of spatiotemporal expression of proteins using BLI. Thermal stress was induced on the raft cultures by means of a constant temperature water bath or with a carbon dioxide (CO2) laser (lambda=10.6 microm, 0.679 to 2.262 Wcm2, cw, unfocused Gaussian beam, omegaL=4.5 mm, 1 min exposure). The bioluminescence was monitored noninvasively with an IVIS 100 Bioluminescent Imaging System. BLI indicated that peak hsp70 expression occurs 4 to 12 h after exposure to thermal stress. A minimum irradiance of 0.679 Wcm2 activated the hsp70 response, and a higher irradiance of 2.262 Wcm2 was associated with a severe reduction in hsp70 response due to tissue ablation. Reverse transcription polymerase chain reaction demonstrated that hsp70 mRNA levels increased with prolonged heating exposures. Enzyme-linked immunosorbent protein assays confirmed that luciferase was an accurate surrogate for hsp70 intracellular protein levels. Hematoxylin and eosin stains verified the presence of the thermally denatured tissue regions. Immunohistochemical analyses confirmed that maximal hsp70 expression occurred at a depth of 150 microm. Bioluminescent microscopy was employed to corroborate these findings. These results indicate that quantitative BLI in engineered tissue equivalents provides a powerful model that enables sequential gene expression studies. Such a model can be used as a high throughput screening platform for laser-tissue interaction studies.
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15 MeSH Terms
Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues.
Pattanayek R, Sethaphong L, Pan C, Prhavc M, Prakash TP, Manoharan M, Egli M
(2004) J Am Chem Soc 126: 15006-7
MeSH Terms: Biomimetic Materials, Crystallography, X-Ray, DNA, Models, Molecular, Nucleic Acid Conformation, RNA, Thymidine
Show Abstract · Added March 5, 2014
Chemical modification of nucleic acids at the 2'-position of ribose has generated antisense oligonucleotides (AONs) with a range of desirable properties. Electron-withdrawing substituents such as 2'-O-[2-(methoxy)ethyl] (MOE) confer enhanced RNA affinity relative to that of DNA by conformationally preorganizing an AON for pairing with the RNA target and by improving backbone hydration. 2'-Substitution of the ribose has also been shown to increase nuclease resistance and cellular uptake via changes in lipophilicity. Interestingly, incorporation of either 2'-O-[2-(methylamino)-2-oxoethyl]- (NMA) or 2'-O-(N-methylcarbamate)-modified (NMC) residues into AONs has divergent effects on RNA affinity. Incorporation of 2'-O-NMA-T considerably improves RNA affinity while incorporation of 2'-O-NMC-T drastically reduces RNA affinity. Crystal structures at high resolution of A-form DNA duplexes containing either 2'-O-NMA-T or 2'-O-NMC-T shed light on the structural origins of the surprisingly large difference in stability given the relatively minor difference in chemistry between NMA and NMC. NMA substituents adopt an extended conformation and use either their carbonyl oxygen or amino nitrogen to trap water molecules between phosphate group and sugar. The conformational properties of NMA and the observed hydration patterns are reminiscent of those found in the structures of 2'-O-MOE-modified RNA. Conversely, the carbonyl oxygen of NMC and O2 of T are in close contact, providing evidence that an unfavorable electrostatic interaction and the absence of a stable water structure are the main reasons for the loss in thermodynamic stability as a result of incorporation of 2'-O-NMC-modified residues.
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7 MeSH Terms
Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA.
Yu L, Oost TK, Schkeryantz JM, Yang J, Janowick D, Fesik SW
(2003) J Am Chem Soc 125: 4444-50
MeSH Terms: Aminoglycosides, Aminoquinolines, Anti-Bacterial Agents, Binding, Competitive, Biomimetic Materials, Escherichia coli, Ligands, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, RNA, Bacterial, RNA, Ribosomal, 16S
Show Abstract · Added March 5, 2014
A method is described for the NMR-based screening for the discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to important microbial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcome the problems associated with toxicities and resistance development observed with the aminoglycosides, we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening of our compound library in search for small-molecule RNA binders against this RNA target. From these studies, several classes of compounds were identified as initial hits with binding affinities in the range of 70 microM to 3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of several small-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides. Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensional structures of the RNA/aminoglycoside complexes.
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11 MeSH Terms