8 research outputs found
Discovering New Acetylcholinesterase Inhibitors by Mining the <i>Buzhongyiqi</i> Decoction Recipe Data
Myasthenia
gravis (MG) is a neuromuscular disease that is conventionally
treated with acetylcholinesterase (AChE) inhibitors, which may not
fully remove the symptom for many reasons. When AChE inhibitors do
not work, Chinese patients turn to Chinese medicine, such as the <i>Buzhongyiqi</i> decoction (BD), to treat MG. By elucidating
the relations between the herbs of the <i>Buzhongyiqi</i> decoction recipe and AChE inhibitors with structure-based and ligand-based
drug design methods and chemoinformatics approaches, we have found
the key active components of BD. Using these key active components
as templates, we have discovered five new AChE inhibitors through
virtual screening of a commercial compound library. The new AChE inhibitors
have been confirmed with Ellman assays. This study demonstrates that
lead identification can be inspired by elucidating Chinese medicine.
Since BD is a mixture, further studies against other drug targets
are needed
Enhancing Glioblastoma-Specific Penetration by Functionalization of Nanoparticles with an Iron-Mimic Peptide Targeting Transferrin/Transferrin Receptor Complex
Treatment
of glioblastoma (GBM) remains to be the most formidable challenge
because of the hindrance of the blood–brain barrier (BBB) along
with the poor drug penetration into the glioma parenchyma. Nanoparticulate
drug delivery systems (DDS) utilizing transferrin (Tf) as the targeting
ligand to target the glioma-associated transferrin receptor (TfR)
had met the problem of loss of specificity in biological environment
due to the high level of endogenous Tf. Here we conjugated CRT peptide,
an iron-mimicry moiety targeting the whole complex of Tf/TfR, to polyÂ(ethylene
glycol)-polyÂ(l-lactic-<i>co</i>-glycolic acid)
nanoparticles (CRT-NP), to open a new route to overcome such obstacle.
High cellular associations, advanced transport ability through the
BBB model, and penetration in 3-dimensional C6 glioma spheroids <i>in vitro</i> had preliminarily proved the advantages of CRT-NP
over Tf-nanoparticle conjugates (Tf-NP). Compared with Tf-NP, NP,
and Taxol, paclitaxel-loaded CRT-NP (CRT-NP-PTX) displayed a superior
antiproliferation effect on C6 glioma cells and stronger inhibitory
effect on glioma spheroids. Favored pharmacokinetics behavior and
enhanced accumulation in glioma foci was observed, together with a
much deeper distribution pattern in glioma parenchyma compared with
unmodified nanoparticles and Tf-NP. Eventually, mice treated with
CRT-NP-PTX showed a remarkably prolonged median survival compared
to those treated with Taxol, NP, or Tf-NP. In conclusion, the modification
of CRT to nanoparticles holds great promise for enhancement of antiglioma
therapy
On the Value of Homology Models for Virtual Screening: Discovering hCXCR3 Antagonists by Pharmacophore-Based and Structure-Based Approaches
Human chemokine receptor CXCR3 (hCXCR3) antagonists have
potential
therapeutic applications as antivirus, antitumor, and anti-inflammatory
agents. A novel virtual screening protocol, which combines pharmacophore-based
and structure-based approaches, was proposed. A three-dimensional
QSAR pharmacophore model and a structure-based docking model were
built to virtually screen for hCXCR3 antagonists. The hCXCR3 antagonist
binding site was constructed by homology modeling and molecular dynamics
(MD) simulation. By combining the structure-based and ligand-based
screenings results, 95% of the compounds satisfied either pharmacophore
or docking score criteria and would be chosen as hits if the union
of the two searches was taken. The false negative rates were 15% for
the pharmacophore model, 14% for the homology model, and 5% for the
combined model. Therefore, the consistency of the pharmacophore model
and the structural binding model is 219/273 = 80%. The hit rate for
the virtual screening protocol is 273/286 = 95%. This work demonstrated
that the quality of both the pharmacophore model and homology model
can be measured by the consistency of the two models, and the false
negatives in virtual screening can be reduced by combining two virtual
screening approaches
Additional file 1: of The potassium channel KCa3.1 constitutes a pharmacological target for astrogliosis associated with ischemia stroke
Figure S1. Cerebral blood flow (CBF) of ischemic brain hemisphere before and during permanent middle cerebral artery occlusion (pMCAO) was monitored by transcranial laser Doppler. The arrow depicted the start of pMCAO. (TIFF 58 kb
On the Value of Homology Models for Virtual Screening: Discovering hCXCR3 Antagonists by Pharmacophore-Based and Structure-Based Approaches
Human chemokine receptor CXCR3 (hCXCR3) antagonists have
potential
therapeutic applications as antivirus, antitumor, and anti-inflammatory
agents. A novel virtual screening protocol, which combines pharmacophore-based
and structure-based approaches, was proposed. A three-dimensional
QSAR pharmacophore model and a structure-based docking model were
built to virtually screen for hCXCR3 antagonists. The hCXCR3 antagonist
binding site was constructed by homology modeling and molecular dynamics
(MD) simulation. By combining the structure-based and ligand-based
screenings results, 95% of the compounds satisfied either pharmacophore
or docking score criteria and would be chosen as hits if the union
of the two searches was taken. The false negative rates were 15% for
the pharmacophore model, 14% for the homology model, and 5% for the
combined model. Therefore, the consistency of the pharmacophore model
and the structural binding model is 219/273 = 80%. The hit rate for
the virtual screening protocol is 273/286 = 95%. This work demonstrated
that the quality of both the pharmacophore model and homology model
can be measured by the consistency of the two models, and the false
negatives in virtual screening can be reduced by combining two virtual
screening approaches
Nanoparticles Coated with Neutrophil Membranes Can Effectively Treat Cancer Metastasis
The
dissemination, seeding, and colonization of circulating tumor
cells (CTCs) serve as the root of distant metastasis. As a key step
in the early stage of metastasis formation, colonization of CTCs in
the (pre-)Âmetastatic niche appears to be a valuable target. Evidence
showed that inflammatory neutrophils possess both a CTC- and niche-targeting
property by the intrinsic cell adhesion molecules on neutrophils.
Inspired by this mechanism, we developed a nanosize neutrophil-mimicking
drug delivery system (NM-NP) by coating neutrophils membranes on the
surface of polyÂ(latic-<i>co</i>-glycolic acid) nanoparticles
(NPs). The membrane-associated protein cocktails on neutrophils membrane
were mostly translocated to the surface of NM-NP <i>via</i> a nondisruptive approach, and the biobinding activity of neutrophils
was highly preserved. Compared with uncoated NP, NM-NP exhibited enhanced
cellular association in 4T1 cell models under shear flow <i>in
vitro</i>, much higher CTC-capture efficiency <i>in vivo</i>, and improved homing to the premetastatic niche. Following loading
with carfilzomib, a second generation of proteasome inhibitor, the
NM-NP-based nanoformulation (NM-NP-CFZ) selectively depleted CTCs
in the blood, prevented early metastasis and potentially inhibited
the progress of already-formed metastasis. Our NP design can neutralize
CTCs in the circulation and inhibit the formation of a metastatic
niche
Lipoprotein-Based Nanoparticles Rescue the Memory Loss of Mice with Alzheimer’s Disease by Accelerating the Clearance of Amyloid-Beta
Amyloid-beta (Aβ) accumulation in the brain is believed to play a central role in Alzheimer’s disease (AD) pathogenesis, and the common late-onset form of AD is characterized by an overall impairment in Aβ clearance. Therefore, development of nanomedicine that can facilitate Aβ clearance represents a promising strategy for AD intervention. However, previous work of this kind was concentrated at the molecular level, and the disease-modifying effectiveness of such nanomedicine has not been investigated in clinically relevant biological systems. Here, we hypothesized that a biologically inspired nanostructure, apolipoprotein E3–reconstituted high density lipoprotein (ApoE3–rHDL), which presents high binding affinity to Aβ, might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance. Surface plasmon resonance, transmission electron microscopy, and co-immunoprecipitation analysis showed that ApoE3–rHDL demonstrated high binding affinity to both Aβ monomer and oligomer. It also accelerated the microglial, astroglial, and liver cell degradation of Aβ by facilitating the lysosomal transport. One hour after intravenous administration, about 0.4% ID/g of ApoE3–rHDL gained access to the brain. Four-week daily treatment with ApoE3–rHDL decreased Aβ deposition, attenuated microgliosis, ameliorated neurologic changes, and rescued memory deficits in an AD animal model. The findings here provided the direct evidence of a biomimetic nanostructure crossing the blood–brain barrier, capturing Aβ and facilitating its degradation by glial cells, indicating that ApoE3–rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance, which also justified the concept that nanostructures with Aβ-binding affinity might provide a novel nanoplatform for AD therapy
GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer’s Disease
Alzheimer’s disease (AD) exerts a heavy health burden for modern society and has a complicated pathological background. The accumulation of extracellular β-amyloid (Aβ) is crucial in AD pathogenesis, and Aβ-initiated secondary pathological processes could independently lead to neuronal degeneration and pathogenesis in AD. Thus, the development of combination therapeutics that can not only accelerate Aβ clearance but also simultaneously protect neurons or inhibit other subsequent pathological cascade represents a promising strategy for AD intervention. Here, we designed a nanostructure, monosialotetrahexosylganglioside (GM1)-modified reconstituted high density lipoprotein (GM1-rHDL), that possesses antibody-like high binding affinity to Aβ, facilitates Aβ degradation by microglia, and Aβ efflux across the blood–brain barrier (BBB), displays high brain biodistribution efficiency following intranasal administration, and simultaneously allows the efficient loading of a neuroprotective peptide, NAP, as a nanoparticulate drug delivery system for the combination therapy of AD. The resulting multifunctional nanostructure, αNAP-GM1-rHDL, was found to be able to protect neurons from Aβ<sub>1–42</sub> oligomer/glutamic acid-induced cell toxicity better than GM1-rHDL <i>in vitro</i> and reduced Aβ deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both αNAP solution and GM1-rHDL in AD model mice following intranasal administration with no observable cytotoxicity noted. Taken together, this work presents direct experimental evidence of the rational design of a biomimetic nanostructure to serve as a safe and efficient multifunctional nanoplatform for the combination therapy of AD