8 research outputs found
Nanosized Aspirin-Arg-Gly-Asp-Val: Delivery of Aspirin to Thrombus by the Target Carrier Arg-Gly-Asp-Val Tetrapeptide
Resistance and nonresponse to aspirin dramatically decreases its therapeutic efficacy. To overcome this issue, a small-molecule thrombus-targeting drug delivery system, aspirin-Arg-Gly-Asp-Val (A-RGDV), is developed by covalently linking Arg-Gly-Asp-Val tetrapeptide with aspirin. The 2D ROESY NMR and ESI-MS spectra support a molecular model of an A-RGDV tetramer. Transmission electron microscopy images suggest that the tetramer spontaneously assembles to nanoparticles (ranging from 5 to 50 nm in diameter) in water. Scanning electron microscopy images and atomic force microscopy images indicate that the smaller nanoparticles of A-RGDV further assemble to bigger particles that are stable in rat blood. The delivery investigation implies that in rat blood A-RGDV is able to keep its molecular integrity, while in a thrombus it releases aspirin. The <i>in vitro</i> antiplatelet aggregation assay suggests that A-RGDV selectively inhibits arachidonic acid induced platelet aggregation. The mechanisms of action probably include releasing aspirin, modifying cyclic oxidase, and decreasing the expression of GPIIb/IIIa. The <i>in vivo</i> assay demonstrates that the effective antithrombotic dose of A-RGDV is 16700-fold lower than the nonresponsive dose of aspirin
Folded Conformation, Cyclic Pentamer, Nanostructure, and PAD4 Binding Mode of YW3-56
The physical and chemical mechanisms
of small molecules with pharmacological activity forming nanostructures
are developing into a new field of nanomedicine. By using ROESY 2D
NMR spectroscopy, tandem mass spectroscopy, transmission electron
microscopy, and computer-assisted molecular modeling, this paper demonstrates
the contribution of the folded conformation, the intra- and intermolecular
π–π stacking, the intra- and intermolecular hydrogen
bonds, and the receptor binding free energy of 6-dimethylaminonaph-2-yl-{<i>N</i>-<i>S</i>-[1-benzylcarba-moyl-4-(2-chloroacetamidobutyl)]-carboxamide
(YW3-56) to the rapid formation of nanorings and the slow formation
of nanocapsules. Thus we have developed a strategy that makes it possible
to elucidate the physical and chemical mechanisms of bioactive small
molecules forming nanostructures
Poly-α,β-dl-Aspartyl‑l‑Cysteine: A Novel Nanomaterial Having a Porous Structure, Special Complexation Capability for Pb(II), and Selectivity of Removing Pb(II)
Poly-α,β-dl-aspartic acid is known
as a green chelant of various metal ions. To provide a novel nanochelant
for treating PbÂ(II) poisoning, poly-α,β-dl-aspartic
acid was modified with l-Cys to form poly-α,β-dl-aspartyl-l-cysteine (PDC; MW, 27273). dl-Asp was converted into polysuccinimide through a thermal polycondensation,
and the amidation of polysuccinimide with l-Cys provided
PDC. In water, PDC formed various porous nanospecies. In the mouse
lead intoxication model, both intraperitoneal and oral administration
of PDC (0.1, 1.0, and 10.0 nmol/kg) dose dependently removed PbÂ(II)
accumulated in the organ, bone, and blood. PDC did not remove the
essential metals including Cu<sup>2+</sup>, Fe<sup>2+</sup>, Mn<sup>2+</sup>, Zn<sup>2+</sup>, and Ca<sup>2+</sup> of the treated mice.
The porous feature and size of the pH- and concentration-dependent
nanospecies of PDC benefited the removal of PbÂ(II)
Synthesis and <i>In Vivo</i> Lead Detoxification Evaluation of Poly-α,β-dl-aspartyl-l-methionine
To increase the metal selectivity of polyaspartic acid,
a so-called
green chelant, poly-α,β-dl-aspartyl-l-methionine (PDM) was synthesized as a novel lead chelating agent.
The phosphoric acid (80%) catalyzed thermal poly condensation of dl-aspartic acid provided poly succinimide, which was amidated
with l-methionine to form PDM (MW: 29161). At the doses of
0.1, 1.0, and 10.0 nmol/kg, either by intraperitoneal injection (i.p.)
or oral administration, PDM removed Pb from the spleens, hearts, and
kidneys of mice, especially dose-dependently decreasing the accumulation
of Pb in the brains, livers, and femurs of the mice, and did not interfere
with the essential metals, including Cu, Fe, Mn, and Ca. Even at the
dose of 0.1 nmol/kg, the i.p. injection of PDM removed Pb from the
spleens, hearts, and kidneys of mice and increased the amount of urinary
volume and urinary Pb, and the amount of fecal matter and the amount
of fecal Pb, resulting in effective removal of Pb from the body of
mice given Pb by i.p. injection. Our findings revealed that in aqueous
solution PDM formed diverse nanospecies
Pyranoflavones: A Group of Small-Molecule Probes for Exploring the Active Site Cavities of Cytochrome P450 Enzymes 1A1, 1A2, and 1B1
Selective inhibition of P450 enzymes
is the key to block the conversion of environmental procarcinogens
to their carcinogenic metabolites in both animals and humans. To discover
highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1,
as well as to investigate active site cavities of these enzymes, 14
novel flavone derivatives were prepared as chemical probes. Fluorimetric
enzyme inhibition assays were used to determine the inhibitory activities
of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly
selective P450 1B1 inhibitor 5-hydroxy-4′-propargyloxyflavone
(5H4′FPE) was discovered. Some tested compounds also showed
selectivity between P450s 1A1 and 1A2. α-Naphthoflavone-like
and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2,
while β-naphthoflavone-like flavone derivatives showed selective
inhibition of P450 1A1. On the basis of structural analysis, the active
site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating
a planar long strip cavity and a planar triangular cavity, respectively
Intrinsic Strain-Mediated Ultrathin Ceria Nanoantioxidant
Metal
oxide nanozymes have emerged as the most efficient
and promising
candidates to mimic antioxidant enzymes for treatment of oxidative
stress-mediated pathophysiological disorders, but the current effectiveness
is unsatisfactory due to insufficient catalytic performance. Here,
we report for the first time an intrinsic strain-mediated ultrathin
ceria nanoantioxidant. Surface strain in ceria with variable thicknesses
and coordinatively unsaturated Ce sites was investigated by theoretical
calculation analysis and then was validated by preparing ∼1.2
nm ultrathin nanoplates with ∼3.0% tensile strain in plane/∼10.0%
tensile strain out of plane. Compared with nanocubes, surface strain
in ultrathin nanoplates could enhance the covalency of the Ce–O
bond, leading to increasing superoxide dismutase (SOD)-mimetic activity
by ∼2.6-fold (1533 U/mg, in close proximity to that of natural
SOD) and total antioxidant activity by ∼2.5-fold. As a proof
of concept, intrinsic strain-mediated ultrathin ceria nanoplates could
boost antioxidation for improved ischemic stroke treatment in vivo, significantly better than edaravone, a commonly
used clinical drug
A Ligand-Based Drug Design. Discovery of 4‑Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2
In
humans, cytochrome P450 1A2 is the major enzyme metabolizing
environmental arylamines or heterocyclic amines into carcinogens.
Since evidence shows that planar triangle-shaped molecules are capable
of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin
derivatives were designed and synthesized for these studies. Among
these compounds, 7,8-furanoflavone time-dependently inhibits P450
1A2 with a <i>K</i><sub>I</sub> value of 0.44 μM.
With a 5 min preincubation in the presence of NADPH, 0.01 μM
7,8-furanoflavone completely inactivates P450 1A2 but does not influence
the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin,
is found to be a competitive inhibitor, showing high selectivity for
the inhibition of P450 1A2 with a <i>K</i><sub>i</sub> of
0.39 μM, 155- and 52-fold lower than its <i>K</i><sub>i</sub> values against P450s 1A1 and 1B1, respectively. In yeast
AhR activation assays, 7,8-pyrano-4-trifluoromethylÂcoumarin
does not activate aryl hydrocarbon receptor when the concentration
is lower than 1 μM, suggesting that this compound would not
up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition
assays show that 7,8-pyrano-4-trifluoromethylÂcoumarin decreases
the MROD activity in HepG2 cells at concentrations higher than 1 μM.
Thus, using 7,8-pyrano-4-trifluoromethylÂcoumarin, a selective
and specific P450 1A2 action suppression could be achieved, indicating
the potential for the development of P450 1A2-targeting cancer preventive
agents
A Ligand-Based Drug Design. Discovery of 4‑Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2
In
humans, cytochrome P450 1A2 is the major enzyme metabolizing
environmental arylamines or heterocyclic amines into carcinogens.
Since evidence shows that planar triangle-shaped molecules are capable
of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin
derivatives were designed and synthesized for these studies. Among
these compounds, 7,8-furanoflavone time-dependently inhibits P450
1A2 with a <i>K</i><sub>I</sub> value of 0.44 μM.
With a 5 min preincubation in the presence of NADPH, 0.01 μM
7,8-furanoflavone completely inactivates P450 1A2 but does not influence
the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin,
is found to be a competitive inhibitor, showing high selectivity for
the inhibition of P450 1A2 with a <i>K</i><sub>i</sub> of
0.39 μM, 155- and 52-fold lower than its <i>K</i><sub>i</sub> values against P450s 1A1 and 1B1, respectively. In yeast
AhR activation assays, 7,8-pyrano-4-trifluoromethylÂcoumarin
does not activate aryl hydrocarbon receptor when the concentration
is lower than 1 μM, suggesting that this compound would not
up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition
assays show that 7,8-pyrano-4-trifluoromethylÂcoumarin decreases
the MROD activity in HepG2 cells at concentrations higher than 1 μM.
Thus, using 7,8-pyrano-4-trifluoromethylÂcoumarin, a selective
and specific P450 1A2 action suppression could be achieved, indicating
the potential for the development of P450 1A2-targeting cancer preventive
agents