Papers by Vladyslav Kholodovych
CD36‐Binding Amphiphilic Nanoparticles for Attenuation of α‐Synuclein‐Induced Microglial Activation
Advanced nanoBiomed research, Mar 22, 2022
Neuroinflammation is one of the hallmarks contributing to Parkinson's disease (PD) pathology,... more Neuroinflammation is one of the hallmarks contributing to Parkinson's disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular α‐synuclein (aSYN) binding to the cluster of differentation 36 (CD36) receptor. Herein, CD36‐binding nanoparticles (NPs) containing tartaric acid–based amphiphilic macromolecules (AMs) are rationally designed to inhibit this aSYN–CD36 binding. In silico docking reveals that four AMs with varying alkyl side chain lengths present differential levels of CD36 binding affinity and that an optimal alkyl chain length promotes the strongest inhibitory activity toward aSYN–CD36 interactions. In vitro competitive binding assays indicate that the inhibitory activity of AM‐based NPs plateaus at intermediate side chain lengths of 12 and 18 carbons, supporting the in silico docking predictions. These intermediate‐length AM NPs also has significantly stronger effects on reducing aSYN internalization and inhibiting proinflammatory molecules tumor necrosis factor α (TNF‐α) and nitric oxide from aSYN‐challenged microglia. All four NPs modulate the gene expression of aSYN‐challenged microglia, downregulating proinflammatory genes TNF, interleukin 6 (IL‐6), and IL‐1β, and upregulating anti‐inflammatory genes transforming growth factor β (TGF‐β) and Arg1 expression. Herein, overall, a novel polymeric nanotechnology platform is represented that can be used to modulate aSYN‐induced microglial activation.
Journal of Medicinal Chemistry, Jul 26, 2016
L-Cystine bismorpholide (1a) and L-cystine bis(N′-methylpiperazide) (1b) were seven and twenty-fo... more L-Cystine bismorpholide (1a) and L-cystine bis(N′-methylpiperazide) (1b) were seven and twenty-four times more effective than L-cystine dimethyl ester (CDME) in increasing the metastable supersaturation range of L-cystine, respectively, effectively inhibiting L-cystine crystallization. This behavior can be attributed to inhibition of crystal growth at microscopic length scale, as revealed by atomic force microscopy. Both 1a and 1b are more stable than CDME, and 1b was effective in vivo in a knockout mouse model of cystinuria.
Structure of human Programmed cell death 1 ligand 1 (PD-L1) with inhibitor
Free Radical Biology and Medicine, Nov 1, 2014
Methods: Acetylcholine (Ach) was administered to sedated rats while monitoring mean systemic arte... more Methods: Acetylcholine (Ach) was administered to sedated rats while monitoring mean systemic arterial pressure (MSAP) and mean pulmonary artery pressure (MPAP). A bolus of either free Hb or Hb-Hp was administered and pressure changes recorded. Histopathological evidence for vascular deposition and localization of Hb was evaluated in smooth muscle tissue from these animals and in vitro. Results: Ach significantly lowered MSAP in the presence of Hb and Hb-Hp. after cessation of Ach infusion free Hb significantly increased MSAP and Hp significantly attenuated this response, Histopathological data indicated that Hb extravasates into vascular tissue and this process is attenuated by Hp. In addition Hp prevents oxidative changes to endothelial cells and vascular tissue. Conclusions: When kept in the plasma compartment, by Hp, Hb does not have access to smooth muscle sites of NO production. Additionally, the acute pathologic effects of Hb within vascular cells are attenuated. Therefore, Hp may be an effective therapy for meditating hemolysis related hypertension and vascular injury.
The tumor neomatrix component fibrillin-1 (FBN1) is a druggable oncologically relevant target: Proof-of-principle in vitro using an FDA-approved medicine as pioneer inhibitor of protein hydroxylation (274)
Gynecologic Oncology, Aug 1, 2022
Biopolymers & Cell, Jan 20, 1999
Abstract 869: Cysteine-based Redox Regulation of Soluble Guanylyl Cyclase
Circulation Research, 2019
Soluble guanylyl cyclase (GC1) is the major receptor of nitric oxide (NO) and a key regulator for... more Soluble guanylyl cyclase (GC1) is the major receptor of nitric oxide (NO) and a key regulator for cardiovascular physiology. NO binding to the heme of GC1 catalyzes conversion of GTP to cGMP, which in turn activates protein kinase G pathway, thus leading to vasodilation. However, the mechanism by which NO signaling is propagated within the GC1 molecule for its stimulation is still poorly understood. The high frequency of solvent-exposed cysteines (Cys) of GC1 suggests a potential role of Cys posttranslational modifications (PTMs) in regulating GC1 activity. Our previous studies show that the disulfide reductase Thioredoxin 1 (Trx1) can interact with GC1 and affect its activity in cells. Together with studies showing that GC1 activity is modulated by thiol redox, we hypothesize that thiol/disulfide switch might be a mechanism that regulates the activity of GC1. Here we show that dithiol oxidant diamide can dose-dependently affect the activity of GC1. PEG-switch assay, LC/MS/MS and mu...
Antimicrobial Agents and Chemotherapy, 2009
Geospatial Phylogenomics bed bugs in NYC-ncomms10164
Applying the drug discovery paradigm to biomaterials
Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cau... more Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cause adverse effects in wildlife and humans. In rodents, PCBs bind to the aryl hydrocarbon (AhR) and pregnane X receptors (PXR) inducing the expression of catabolic cytochrome p450 enzymes of the CYP1A and 3A families. We found that certain highly chlorinated PCBs are potent activators of rodent PXR but antagonize its human ortholog, the steroid and xenobiotic receptor (SXR), inhibiting target gene induction. Thus, exposure to PCBs may blunt the human xenobiotic response, inhibiting the detoxification of steroids, bioactive dietary compounds, and xenobiotics normally mediated by SXR. The antagonistic PCBs are among the most stable and abundant in human tissues. These findings have important implications for understanding the biologic effects of PCB exposure and the use of animal models to predict the attendant risk.
Journal of Medicinal Chemistry, 2019
A series of C 2-symmetric inhibitors was designed and evaluated for inhibitory activity against t... more A series of C 2-symmetric inhibitors was designed and evaluated for inhibitory activity against the PD-1/PD-L1 protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cellbased co-culture assays. C 2-symmetric inhibitors 2a (LH1306) and 2b (LH1307) exhibited IC 50 's of 25 and 3.0 nM, respectively, in the HTRF assay. While 2a was ~3.8-fold more potent than previously reported inhibitor 1a, 2b could not be differentiated from 1b due to their high potency and the limit of our HTRF assay conditions. In one cell-based coculture PD-1 signaling assay, 2a and 2b were 8.2-and 2.8-fold more potent in inhibiting PD-1 signaling than 1a and 1b, respectively. NMR and X-ray co-crystal structural studies provided more structural insights into the interaction between 2b and PD-L1; 2b binds to PD-L1 at the PD-1 binding site and induces the formation of a more symmetrically arranged PD-L1 homodimer than previously reported for other inhibitors.
Biochemistry, Jul 11, 2017
The heterodimeric human immunodeficiency virus type 1 reverse transcriptase is composed of p66 an... more The heterodimeric human immunodeficiency virus type 1 reverse transcriptase is composed of p66 and p51 subunits. While in the p51 subunit, the connection domain is tucked in the polymerase cleft; it is effectively displaced from the cleft of the catalytically active p66 subunit. How is the connection domain relocated from the polymerase cleft of p66? Does the RNase H domain have any role in this process? To answer this question, we extended the C-terminal region of p51 by stepwise addition of N-terminal motifs of RNase H domain to generate p54, p57, p60, and p63 derivatives. We found all of the C-terminal extended derivatives of p51 assume open conformation, bind to the template-primer, and catalyze the polymerase reaction. Glycerol gradient ultracentrifugation analysis showed that only p54 sedimented as a monomer, while other derivatives were in a homodimeric conformation. We proposed a model to explain the monomeric conformation of catalytically active p54 derivative carrying addi...
Proceedings of the National Academy of Sciences, 2015
Significance Lipid-rich plaques in major blood vessels recruit macrophages that further exacerbat... more Significance Lipid-rich plaques in major blood vessels recruit macrophages that further exacerbate the lipid burden and risk of heart attacks or stroke. A local approach to prevent plaque growth has yet to be successfully deployed. In this study, we examine how synthetic ligands counteract macrophage atherogenesis and de-escalate plaque burden. Using a library of sugar-based amphiphilic core-shell layered nanoparticles, we demonstrate the design principles necessary to prevent oxidized lipid uptake and suppress scavenger receptor expression in macrophages, switching them to an “atheroprotective” phenotype. When administered in vivo, nanoparticles were retained at atherosclerotic lesions, where they mitigated cholesterol clefts, inflammation, and artery occlusion. Thus, synthetic nanomedicines could be used to potentially treat acute coronary syndrome, a major unmet need in cardiovascular diseases.
Journal of Molecular Graphics and Modelling, 2007
Volume learning algorithm (VLA) artificial neural network and partial least squares (PLS) methods... more Volume learning algorithm (VLA) artificial neural network and partial least squares (PLS) methods were compared using the leave-one-out cross-validation procedure for prediction of relative potency of xenoestrogenic compounds to the estrogen receptor. Using Wilcoxon signed rank test we showed that VLA outperformed PLS by producing models with statistically superior results for a structurally diverse set of compounds comprising eight chemical families. Thus, CoMFA/VLA models are successful in prediction of the endocrine disrupting potential of environmental pollutants and can be effectively applied for testing of prospective chemicals prior their exposure to the environment.
Journal of Chemical Information and Computer Sciences, 1998
Cascade Learning (CL) [20] is a new adaptive approach to train deep neural networks. It is partic... more Cascade Learning (CL) [20] is a new adaptive approach to train deep neural networks. It is particularly suited to transfer learning, as learning is achieved in a layerwise fashion, enabling the transfer of selected layers to optimize the quality of transferred features. In the domain of Human Activity Recognition (HAR), where the consideration of resource consumption is critical, CL is of particular interest as it has demonstrated the ability to achieve significant reductions in computational and memory costs with negligible performance loss. In this paper, we evaluate the use of CL and compare it to end to end (E2E) learning in various transfer learning experiments, all applied to HAR. We consider transfer learning across objectives, for example opening the door features transferred to opening the dishwasher. We additionally consider transfer across sensor locations on the body, as well as across datasets. Over all of our experiments, we find that CL achieves state of the art performance for transfer learning in comparison to previously published work, improving F 1 scores by over 15%. In comparison to E2E learning, CL performs similarly considering F 1 scores, with the additional advantage of requiring fewer parameters. Finally, the overall results considering HAR classification performance and memory requirements demonstrate that CL is a good approach for transfer learning.
Journal of computer-aided molecular design, 2011
The Online Chemical Modeling Environment is a web-based platform that aims to automate and simpli... more The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute thei...
Environmental Health Perspectives, 2003
Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cau... more Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cause adverse effects in wildlife and humans. In rodents, PCBs bind to the aryl hydrocarbon (AhR) and pregnane X receptors (PXR) inducing the expression of catabolic cytochrome p450 enzymes of the CYP1A and 3A families. We found that certain highly chlorinated PCBs are potent activators of rodent PXR but antagonize its human ortholog, the steroid and xenobiotic receptor (SXR), inhibiting target gene induction. Thus, exposure to PCBs may blunt the human xenobiotic response, inhibiting the detoxification of steroids, bioactive dietary compounds, and xenobiotics normally mediated by SXR. The antagonistic PCBs are among the most stable and abundant in human tissues. These findings have important implications for understanding the biologic effects of PCB exposure and the use of animal models to predict the attendant risk.
Abstract A13: Discovery of selective inhibitors of the kinase and metastatic activities of the activated Cdc42-associated kinase (ACK1)
Clinical Cancer Research, 2010
Activated Cdc42-associated kinase (ACK1) is a non-receptor tyrosine kinase and an effector protei... more Activated Cdc42-associated kinase (ACK1) is a non-receptor tyrosine kinase and an effector protein of Cdc42. Previous reports have demonstrated that ACK1 is a critical factor in the cellular transformation of a number of cancer cell lines. ACK1 also contributes to cellular motility, and overexpression in certain cell lines results in enhanced motility. The significance of tyrosine kinase proteins such as ACK1 in cancer-related signaling pathways, and the implications of metastasis in the prognosis of cancer patients, point to the importance of the discovery of a potent yet selective inhibitor for this protein. As a result, we are engaged in a study focused on applying computational approaches to identify novel inhibitor molecules of ACK that will also hamper its ability to promote motility of cancer cells. We employed customized in-house computational tools to retrieve approximately 50 small-molecule hits from our chemical databases that may bind with high affinity to the ACK1 ATP b...
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Papers by Vladyslav Kholodovych