7 research outputs found
Self-Assembled Nanostructures of Peptide Amphiphiles: Charge Regulation by Size Regulation
Self-assembled nanostructures of peptide amphiphiles (PAs) with molecular structures C16K2 and C16K3 (where C indicates the number of carbon atoms in the alkyl chain and K is the lysine in the head group) were studied by a combination of theoretical modeling, transmission electron and atomic force microscopes, and acid-base titration experiments. The supramolecular morphology of the PAs (micelles, fibers, or lamellas) was dependent on the pH and ionic strength of the solution. Theoretical modeling was performed using a molecular theory that allows determining the equilibrium morphology, the size, and the charge of the soft nanoassemblies as a function of the molecular structure of the PA, and the pH and salt concentration of the solution. Theoretical predictions showed good agreement with experimental data for the pH-dependent morphology and size of the nanoassemblies and their apparent pKa's. Two interesting effects associated with charge regulation mechanisms were found: first, ionic strength plays a dual role in the modulation of the electrostatic interactions in the system, which leads to complex dependencies of the aggregation numbers with salt concentration; second, the aggregation number of the nanostructures decreases upon increasing the charge per PA. The second mechanism, charge regulation by size regulation, tunes the net charge of the assemblies to decrease the electrostatic repulsions. A remarkable consequence of this behavior is that adding an extra lysine residue to the charged region of the PAs can lead to an unexpected decrease in the total charge of the micelles.Fil: Zaldivar, Gervasio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Vemulapalli, Sridhar. University Of Nebraska Medical Center; Estados UnidosFil: Udumula, Venkatareddy. University Of Nebraska Medical Center; Estados UnidosFil: Conda Sheridan, Martin. University Of Nebraska Medical Center; Estados UnidosFil: Tagliazucchi, Mario Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin
Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.
The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Förster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials
Investigation of Antibacterial Mode of Action for Traditional and Amphiphilic Aminoglycosides
Aminoglycoside represents a class of versatile and broad spectrum antibacterial agents. In an effort to revive the antibacterial activity against aminoglycoside resistant bacteria, our laboratory has developed two new classes of aminoglycoside, pyranmycin and amphiphilic neomycin (NEOF004). The former resembles the traditional aminoglycoside, neomycin. The latter, albeit derived from neomycin, appears to exert antibacterial action via a different mode of action. In order to discern that these aminoglycoside derivatives have distinct antibacterial mode of action, RNA-binding affinity and fluorogenic dye were employed. These studies, together with our previous investigation, confirm that pyranmycin exhibit the traditional antibacterial mode of action of aminoglycosides by binding toward the bacterial rRNA. On the other hand, the amphiphilic neomycin, NEOF004 disrupts the bacterial cell wall. In a broader perspective, it verifies that structurally modified neomycin can exert different antibacterial mode of action leading to the revival of activity against aminoglycoside resistant bacteria
Chemo- and Site-Selective Alkyl and Aryl Azide Reductions with Heterogeneous Nanoparticle Catalysts
Site-selective modification
of bioactive natural products is an
effective approach to generating new leads for drug discovery. Herein,
we show that heterogeneous nanoparticle catalysts enable site-selective
monoreduction of polyazide substrates for the generation of aminoglycoside
antibiotic derivatives. The nanoparticle catalysts are highly chemoselective
for reduction of alkyl and aryl azides under mild conditions and in
the presence of a variety of easily reduced functional groups. High
regioselectivity for monoazide reduction is shown to favor reduction
of the least sterically hindered azide. We hypothesize that the observed
selectivity is derived from the greater ability of less-hindered azide
groups to interact with the surface of the nanoparticle catalyst.
These results are complementary to previous Staudinger reduction methods
that report a preference for selective reduction of electronically
activated azides
Dual Optimization Approach to Bimetallic Nanoparticle Catalysis: Impact of M<sub>1</sub>/M<sub>2</sub> Ratio and Supporting Polymer Structure on Reactivity
A dual
optimization approach to nanoparticle catalysis is reported
in which both the composition of a bimetallic nanoparticle and the
electronic properties of the supporting polystyrene-based polymer
can be varied to optimize reactivity and chemoselectivity in nitroarene
reductions. Ruthenium–cobalt nanoparticles supported on polystyrene
are shown to catalyze nitroarene reductions at room temperature with
exceptional activity, as compared with monometallic ruthenium catalysts.
Both the identity of the second metal and the M<sub>1</sub>/M<sub>2</sub> ratio show a profound effect on the chemoselectivity of nitroarene
reductions. These polymer-supported bimetallic catalysts are shown
to react with nearly complete chemoselectivity for nitro group reduction
over a variety of easily reducible functional groups. The electronic
properties of the supporting polymer also have a significant impact
on catalysis, in which electron-deficient polystyrenes enable 100%
conversion to the aniline product in just 20 min at room temperature.
Polymer effects are also shown to influence the mechanism of the reduction
reaction, in addition to accelerating the rate, confirming the impact
of the polymer structure on catalytic efficiency. These catalysts
are easily prepared in a single step from commercial materials and
can be readily recycled without loss of activity
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Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.
The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Förster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials
Recommended from our members
Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.
The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Förster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials