Papers by Yuri K Peterson
Communications Biology
Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Li... more Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), which can cause severe cardiovascular disease. Statins, bile acid sequestrants, PCSK9 inhibitors, and cholesterol absorption inhibitors are all inefficient at treating FH patients with homozygous LDLR gene mutations (hoFH). Drugs approved for hoFH treatment control lipoprotein production by regulating steady-state Apolipoprotein B (apoB) levels. Unfortunately, these drugs have side effects including accumulation of liver triglycerides, hepatic steatosis, and elevated liver enzyme levels. To identify safer compounds, we used an iPSC-derived hepatocyte platform to screen a structurally representative set of 10,000 small molecules from a proprietary library of 130,000 compounds. The screen revealed molecules that could reduce the secretion of apoB from cultured hepatocytes and from humanized livers in mice. These small molecules are highly effective, do not ca...
Chemical Science
Small molecule inhibitors of CD38 promote increases in interferon gamma and stimulate natural kil... more Small molecule inhibitors of CD38 promote increases in interferon gamma and stimulate natural killer cell proliferation for the treatment of neuroblastoma.
2020 IEEE International Conference on Big Data (Big Data), 2020
This paper presents results from a rapid-response industry-academia collaboration for virtual scr... more This paper presents results from a rapid-response industry-academia collaboration for virtual screening of chemical, natural and virtual drug ligands towards identifying potential therapeutics for COVID-19. Compared to resource-intensive traditional approaches of either conducting high- throughput screening in a lab or in-silico molecular dynamics simulations on supercomputers, we have developed an open- source framework that leverages artificial intelligence (AI) to accurately and quickly predict the binding potential of a drug ligand with a target protein. We have trained a novel molecular-highway graph neural network architecture using the entirety of the BindingDB database to predict the probability of a drug ligand binding to a protein target. Our approach achieves a prodigious 98.3% accuracy with its predictions. Through this paper, we disseminate our source code and use the AI model to screen both public (ChEMBL, DrugBank) and proprietary databases. Compared to other AI-based methods, our approach outperforms the state-of-the-art on the following metrics - (i) number of molecules currently undergoing active clinical trials, (ii) number of antiviral drugs correctly identified, (iii) accuracy despite not needing active-site priors, and (iv) ability to screen more compounds in unit time.
Purpose: Metabolic stress and associated mitochondrial dysfunction are implicated in retinal dege... more Purpose: Metabolic stress and associated mitochondrial dysfunction are implicated in retinal degeneration irrespective of the underlying cause. We identified seven unique chemicals from a Chembridge DiverSET screen and tested their protection against photoreceptor cell death in cell-and animal-based approaches. Methods: Calcium overload (A23187) was triggered in 661W murine photoreceptor-derived cells, and changes in redox potential and real-time changes in cellular metabolism were assessed using the MTT and Seahorse Biosciences XF assay, respectively. Cheminformatics to compare structures, and biodistribution in the living pig eye aided in selection of the lead compound. In-situ, retinal organ cultures of rd1 mouse and S334ter-line-3 rat were tested, in-vivo the light-induced retinal degeneration in albino Balb/c mice was used, assessing photoreceptor cell numbers histologically. Results: Of the seven chemicals, six were protective against A23187-and IBMX-induced loss of mitochondrial capacity, as measured by viability and respirometry in 661W cells. Cheminformatic analyses identified a unique pharmacophore with 6 physico-chemical features based on two compounds (CB11 and CB12). The protective efficacy of CB11 was further shown by reducing photoreceptor cell loss in retinal explants from two retinitis pigmentosa rodent models. Using eye drops, CB11 targeting to the pig retina was confirmed. The same eye drops decreased photoreceptor cell loss in light-stressed Balb/c mice. Conclusions: New chemicals were identified that protect from mitochondrial damage and lead to improved mitochondrial function. Using ex-vivo and in-vivo models, CB11 decreased the loss of photoreceptor cells in murine models of retinal degeneration and may be effective as treatment for different retinal dystrophies.
MedChemComm, 2019
Dual inhibitors of LSD1 and SMOX, with no activity against N1-acetylpolyamine oxidase (PAOX).
Cancer Research, 2017
The RNA-binding protein La is overexpressed in a number of tumor tissues and is proposed to suppo... more The RNA-binding protein La is overexpressed in a number of tumor tissues and is proposed to support tumorigenesis via binding to mRNAs encoding tumor-promoting and anti-apoptotic factors to facilitate their translation. Our data suggest that those mRNAs might need La to be translated mainly in a cap-independent mechanism in cancer cells. Hence, small molecules able to block the binding of La to specific RNAs could represent a novel therapeutic strategy for cancer treatment. In an attempt toward this approach we developed a high-throughput fluorescence polarization assay to screen small compound libraries for molecules inhibiting the binding of La to an RNA element derived from cyclin D1 mRNA. Herein we describe a robust fluorescence polarization assay and the validation of primary hits by electrophoretic mobility shift assays. Using isothermal titration calorimetry we show that a compound binds to La and molecular modeling suggests an interaction between the compound and the RNA rec...
Angiogenesis, 2017
Secreted frizzled-related protein 2 (SFRP2) is a pro-angiogenic factor expressed in the vasculatu... more Secreted frizzled-related protein 2 (SFRP2) is a pro-angiogenic factor expressed in the vasculature of a wide variety of human tumors, and modulates angiogenesis via the calcineurin-dependent Nuclear Factor of Activated T-cells cytoplasmic 3 (NFATc3) pathway in endothelial cells. However, until now, SFRP2 receptor for this pathway was unknown. In the present study, we first used amino acid alignments and molecular modeling to demonstrate that SFRP2 interaction with frizzled-5 (FZD5) is typical of Wnt/FZD family members. To confirm this interaction, we performed co-immunofluorescence, co-immunoprecipitation, and ELISA binding assays, which demonstrated SFRP2/FZD5 binding. Functional knock-down studies further revealed that FZD5 is necessary for SFRP2-induced tube formation and intracellular calcium flux in endothelial cells. Using protein analysis on endothelial cell nuclear extracts, we also discovered that FZD5 is required for SFRP2-induced activation of NFATc3. Our novel findings reveal that FZD5 is a receptor for SFRP2, and mediates SFRP2-induced angiogenesis via calcineurin/NFATc3 pathway in endothelial cells.
Journal of medicinal chemistry, Jan 18, 2016
One of the biggest hurdles yet to be overcome for the continued improvement of Histone Deacetylas... more One of the biggest hurdles yet to be overcome for the continued improvement of Histone Deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations. With the goal of developing a second generation of HDAC inhibitors, lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of our lead analogs' efficacy, selectivity, and toxicity profiles demonstrate they possess low nanomolar activity against models of Acute Myeloid Leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such ...
Encyclopedia of Signaling Molecules, 2012
Glucose-and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pa... more Glucose-and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure beta cells. Evidence for an essential role of GTP-binding proteins in nutrient-induced insulin secretion.
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
Encyclopedia of Signaling Molecules, 2012
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Papers by Yuri K Peterson