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https://www.readbyqxmd.com/read/29677189/progress-in-the-pharmacological-treatment-of-human-cystic-and-alveolar-echinococcosis-compounds-and-therapeutic-targets
#1
Mar Siles-Lucas, Adriano Casulli, Roberto Cirilli, David Carmena
Human cystic and alveolar echinococcosis are helmintic zoonotic diseases caused by infections with the larval stages of the cestode parasites Echinococcus granulosus and E. multilocularis, respectively. Both diseases are progressive and chronic, and often fatal if left unattended for E. multilocularis. As a treatment approach, chemotherapy against these orphan and neglected diseases has been available for more than 40 years. However, drug options were limited to the benzimidazoles albendazole and mebendazole, the only chemical compounds currently licensed for treatment in humans...
April 20, 2018: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29676924/paclitaxel-loaded-ph-sensitive-liposome-new-insights-on-structural-and-physicochemical-characterization
#2
Liziane Oliveira Fonseca Monteiro, Angelo Malachias, Gwenaelle Pound-Lana, Rogerio Magalhães-Paniago, Vanessa Carla Furtado Mosqueira, Mônica Cristina Oliveira, Andre Branco de Barros, Elaine Amaral Leite
A long-circulating and pH-sensitive liposome containing PTX (SpHL-PTX) was recently developed by our group. Once at an acidic environment, e.g. tumor, these liposomes undergo destabilization releasing the encapsulated drug. In this way, the aim of this study was evaluate the molecular and supramolecular interactions between the lipid bilayer and PTX in similar biological environment conditions. High sensitivity analyses of SpHL-PTX structures were obtained by small angle X-ray scattering (SAXS) technique combined with other techniques such as DLS, AF4, TEM and HPLC...
April 20, 2018: Langmuir: the ACS Journal of Surfaces and Colloids
https://www.readbyqxmd.com/read/29676907/%C3%AE-glucocerebrosidase-modulators-promote-dimerization-of-%C3%AE-glucocerebrosidase-and-reveal-an-allosteric-binding-site
#3
Jianbin Zheng, Long Chen, Owen S Skinner, Daniel Ysselstein, Jonathan Remis, Peter Lansbury, Renato Skerlj, Michael Mrosek, Ursula Heunisch, Stephan Krapp, Joel Charrow, Michael Schwake, Neil L Kelleher, Richard B Silverman, Dimitri Krainc
β-Glucocerebrosidase (GCase) mutations cause Gaucher's disease and are a high risk factor in Parkinson's disease. The implementation of a small molecule modulator is a strategy to restore proper folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, JZ-4109, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (JZ-5029) for in vitro mechanistic studies...
April 20, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29676732/donated-chemical-probes-for-open-science
#4
Susanne Müller, Suzanne Ackloo, Cheryl H Arrowsmith, Marcus Bauser, Jeremy L Baryza, Julian Blagg, Jark Böttcher, Chas Bountra, Peter J Brown, Mark E Bunnage, Adrian J Carter, David Damerell, Volker Dötsch, David H Drewry, Aled M Edwards, James Edwards, Jon M Elkins, Christian Fischer, Stephen V Frye, Andreas Gollner, Charles E Grimshaw, Adriaan IJzerman, Thomas Hanke, Ingo V Hartung, Steve Hitchcock, Trevor Howe, Terry V Hughes, Stefan Laufer, Volkhart Mj Li, Spiros Liras, Brian D Marsden, Hisanori Matsui, John Mathias, Ronan C O'Hagan, Dafydd R Owen, Vineet Pande, Daniel Rauh, Saul H Rosenberg, Bryan L Roth, Natalie S Schneider, Cora Scholten, Kumar Singh Saikatendu, Anton Simeonov, Masayuki Takizawa, Chris Tse, Paul R Thompson, Daniel K Treiber, Amélia Yi Viana, Carrow I Wells, Timothy M Willson, William J Zuercher, Stefan Knapp, Anke Mueller-Fahrnow
Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose...
April 20, 2018: ELife
https://www.readbyqxmd.com/read/29676157/high-throughput-assay-for-collagen-secretion-suggests-an-unanticipated-role-for-hsp90-in-collagen-production
#5
Madeline Y Wong, Ngoc Duc Doan, Andrew S DiChiara, Louis J Papa, Jaime H Cheah, Christian K Soule, Nicki Watson, John D Hulleman, Matthew D Shoulders
Collagen overproduction is a feature of fibrosis and cancer, while insufficient deposition of functional collagen molecules and/or the secretion of malformed collagen are common in genetic disorders like osteogenesis imperfecta. Collagen secretion is an appealing therapeutic target in these and other diseases, as secretion directly connects intracellular biosynthesis to collagen deposition and biological function in the extracellular matrix. However, small molecule and biological methods to tune collagen secretion are severely lacking...
April 20, 2018: Biochemistry
https://www.readbyqxmd.com/read/29676014/autoinflammatory-disease-in-the-lung
#6
REVIEW
Thomas Scambler, Jonathan Holbrook, Sinisa Savic, Michael F McDermott, Daniel Peckham
Ascertaining the dominant cell type driving an immunological disease is essential to understanding the causal pathology and, therefore, selecting or developing an effective treatment. Classifying immunological diseases in this way has led to successful treatment regimens for many monogenic diseases; however, when the dominant cell type is unclear and there is no obvious causal genetic mutation, then identifying the correct disease classification and appropriate therapy can be challenging. In this review we focus on pulmonary immunological diseases where an innate immune signature has been identified as a predominant aspect of the immunopathology...
April 19, 2018: Immunology
https://www.readbyqxmd.com/read/29675521/highly-sensitive-and-specific-electrochemical-biosensor-for-microrna-21-detection-by-coupling-catalytic-hairpin-assembly-with-rolling-circle-amplification
#7
Qing Li, Fanpeng Zeng, Nan Lyu, Jun Liang
BACKGROUND: MicroRNA plays a significant role in gene regulation and is usually regarded as an important biological marker. Electrochemical biosensors are excellent tools for microRNA detection. METHODS: In this experiment, we take miRNA-21 as a target, combining catalytic hairpin assembly (CHA) and rolling circle amplification (RCA) as a dual signal amplification strategy for the detection of microRNA in an electrochemical biosensor. RESULTS: This strategy has a good linear range of 0...
April 20, 2018: Analyst
https://www.readbyqxmd.com/read/29675250/novel-dual-function-near-infrared-ii-fluorescence-and-pet-probe-for-tumor-delineation-and-image-guided-surgery
#8
Yao Sun, Xiaodong Zeng, Yuling Xiao, Changhao Liu, Hua Zhu, Hui Zhou, Ziyang Chen, Fuchun Xu, Jule Wang, Mengyue Zhu, Junzhu Wu, Mei Tian, Hong Zhang, Zixin Deng, Zhen Cheng, Xuechuan Hong
Accurate tumor identification is essential in cancer management. Incomplete excision of tumor tissue, however, negatively affects the prognosis of the patient. To accomplish radical excision of tumor tissue, radiotracers can be used that target tumor tissue and can be detected using a gamma probe during surgery. Intraoperative fluorescence imaging could allow accurate real-time tumor delineation. Herein, a novel dual-modal imaging platform using base-catalyzed double addition of thiols into a propiolamide scaffold has been developed, allowing for the highly efficient and selective assembly of various thiol units in a protecting-group-free manner...
February 28, 2018: Chemical Science
https://www.readbyqxmd.com/read/29675145/advances-in-targeting-the-folate-receptor-in-the-treatment-imaging-of-cancers
#9
REVIEW
Marcos Fernández, Faiza Javaid, Vijay Chudasama
The folate receptor (FR) is a recognised biomarker for tumour cells due to its overexpression on a large number of tumours. Consequently, the FR has been exploited by many diagnostic and therapeutic tools to allow targeted delivery to, and imaging of, cancer cells. Herein, we describe the many different approaches by which this has been achieved, including the attachment of folate to potent chemotherapeutic drugs to form FR-targeting small molecule-drug conjugates (SMDCs), FR-targeting antibodies (as antibody alone and as an antibody-drug conjugate), and in the form of complementary nanotechnology-folate platforms; as well as imaging variants thereof...
January 28, 2018: Chemical Science
https://www.readbyqxmd.com/read/29674848/biofilm-infections-between-scylla-and-charybdis-interplay-of-host-antimicrobial-peptides-and-antibiotics
#10
Sergey Chernysh, Natalia Gordya, Dmitry Tulin, Andrey Yakovlev
Purpose: The aim of this study is to improve the anti-biofilm activity of antibiotics. We hypothesized that the antimicrobial peptide (AMP) complex of the host's immune system can be used for this purpose and examined the assumption on model biofilms. Methods: FLIP7, the AMP complex of the blowfly Calliphora vicina containing a combination of defensins, cecropins, diptericins and proline-rich peptides was isolated from the hemolymph of bacteria-challenged maggots...
2018: Infection and Drug Resistance
https://www.readbyqxmd.com/read/29674445/druggable-negative-allosteric-site-of-p2x3-receptors
#11
Jin Wang, Yao Wang, Wen-Wen Cui, Yichen Huang, Yang Yang, Yan Liu, Wen-Shan Zhao, Xiao-Yang Cheng, Wang-Sheng Sun, Peng Cao, Michael X Zhu, Rui Wang, Motoyuki Hattori, Ye Yu
Allosteric modulation provides exciting opportunities for drug discovery of enzymes, ion channels, and G protein-coupled receptors. As cation channels gated by extracellular ATP, P2X receptors have attracted wide attention as new drug targets. Although small molecules targeting P2X receptors have entered into clinical trials for rheumatoid arthritis, cough, and pain, negative allosteric modulation of these receptors remains largely unexplored. Here, combining X-ray crystallography, computational modeling, and functional studies of channel mutants, we identified a negative allosteric site on P2X3 receptors, fostered by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains...
April 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29674376/cherchez-la-femme-impact-of-ocean-acidification-on-the-egg-jelly-coat-and-attractants-for-sperm
#12
Shawna A Foo, Dione Deaker, Maria Byrne
The impact of ocean acidification on marine invertebrate eggs and consequences for sperm chemotaxis are unknown. In the sea urchins Heliocidaris tuberculata and H. erythrogramma , with small (93µm) and large (393µm) eggs, respectively, we documented the effect of decreased pH on the egg jelly coat, an extracellular matrix that increases target size for sperm and contains sperm attracting molecules. In near future conditions (pH 7.8, 7.6) the jelly coat of H. tuberculata decreased by 11 and 21%, reducing egg target size by 9 and 17%, respectively...
April 19, 2018: Journal of Experimental Biology
https://www.readbyqxmd.com/read/29674291/molecular-modeling-on-porphyrin-derivatives-as-%C3%AE-5-subunit-inhibitor-of-20s-proteasome
#13
Muhammad Arba, Andry Nur-Hidayat, Ruslin, Muhammad Yusuf, Sumarlin, Rukman Hertadi, Setyanto Tri Wahyudi, Slamet Ibrahim Surantaadmaja, Daryono H Tjahjono
The ubiquitin-proteasome system plays an important role in protein quality control. Currently, inhibition of the proteasome has been validated as a promising approach in anticancer therapy. The 20S core particle of the proteasome harbors β5 subunit which is a crucial active site in proteolysis. Targeting proteasome β5 subunit which is responsible for the chymotrypsin-like activity of small molecules has been regarded as an important way for achieving therapeutics target. In the present study, a series of porphyrin derivatives bearing either pyridine or pyrazole rings as meso-substituents were designed and evaluated as an inhibitor for the β5 subunit of the proteasome by employing molecular docking and dynamics simulations...
April 16, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29673805/effect-of-n-acetylgalactosamine-ligand-valency-on-targeting-dendrimers-to-hepatic-cancer-cells
#14
Sibu P Kuruvilla, Gopinath Tiruchinapally, Neha Kaushal, Mohamed E H ElSayed
The display of N-acetylgalactosamine (NAcGal) ligands has shown great potential in improving the targeting of various therapeutic molecules to hepatocellular carcinoma (HCC), a severe disease whose clinical treatment is severely hindered by limitations in delivery of therapeutic cargo. We previously used the display of NAcGal on generation 5 (G5) polyamidoamine (PAMAM) dendrimers connected through a poly(ethylene glycol) (PEG) brush (i.e. G5-cPEG-NAcGal; monoGal) to effectively target hepatic cancer cells and deliver a loaded therapeutic cargo...
April 16, 2018: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29673715/optimized-allosteric-inhibition-of-engineered-protein-tyrosine-phosphatases-with-an-expanded-palette-of-biarsenical-small-molecules
#15
Samuel Korntner, Adam Pomorski, Artur Krężel, Anthony C Bishop
Protein tyrosine phosphatases (PTPs), which catalyze the dephosphorylation of phosphotyrosine in protein substrates, are important cell-signaling regulators, as well as potential drug targets for a range of human diseases. Chemical tools for selectively targeting the activities of individual PTPs would help to elucidate PTP signaling roles and potentially expedite the validation of PTPs as therapeutic targets. We have recently reported a novel strategy for the design of non-natural allosteric-inhibition sites in PTPs, in which a tricysteine moiety is engineered within the PTP catalytic domain at a conserved location outside of the active site...
April 12, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29673714/discovery-and-evaluation-of-nna-v-1-5-sodium-channel-blockers-with-potent-cell-invasion-inhibitory-activity-in-breast-cancer-cells
#16
Shilpa Dutta, Osbaldo Lopez Charcas, Samuel Tanner, Frédéric Gradek, Virginie Driffort, Sébastien Roger, Katri Selander, Sadanandan E Velu, Wayne Brouillette
Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be associated with metastatic behavior in a variety of human cancers. The neonatal isoform of the VGSC subtype, Nav 1.5 (nNav 1.5) is overexpressed in the highly aggressive human breast cancer cell line, MDA-MB-231...
April 3, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29672908/molecular-insights-into-trypanothione-reductase-inhibitor-interaction-a-structure-based-review
#17
REVIEW
Neha Tiwari, Neetu Tanwar, Manoj Munde
Information on how small molecules bind to the target enzyme has the potential to impact immensely on how medicinal chemists go about antiparasitic drug discovery. In this review, for the first time, we intend to make an assessment of the structural aspects of trypanothione reductase as drug target, and its complexes with several reversible drugs from the Protein Data Bank (PDB). We attempt to reveal the mechanism of these interactions by careful accounting of the X-ray structures and their possible roles in biological activity to treat Trypanosomatidae diseases...
April 19, 2018: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29672874/review-article-novel-oral-targeted-therapies-in-inflammatory-bowel-disease
#18
REVIEW
J R White, F Phillips, T Monaghan, W Fateen, S Samuel, S Ghosh, G W Moran
BACKGROUND: There is a great unmet clinical need for efficacious, tolerable, economical and orally administrated drugs for the treatment of inflammatory bowel disease (IBD). New therapeutic avenues have become possible including the development of medications that target specific genetic pathways found to be relevant in other immune mediated diseases. AIMS: To provide an overview of recent clinical trials for new generation oral targeted medications that may have a future role in IBD management...
April 19, 2018: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29672864/menin-regulates-the-serine-biosynthetic-pathway-in-ewing-sarcoma
#19
Laurie K Svoboda, Selina Shiqing K Teh, Sudha Sud, Samuel Kerk, Aaron Zebolsky, Sydney Treichel, Dafydd Thomas, Christopher J Halbrook, Ho-Joon Lee, Daniel Kremer, Li Zhang, Szymon Klossowski, Armand R Bankhead, Brian Magnuson, Mats Ljungman, Tomasz Cierpicki, Jolanta Grembecka, Costas A Lyssiotis, Elizabeth R Lawlor
Developmental transcription programs are epigenetically regulated by multi-protein complexes, including the menin- and MLL-containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and function as oncogenes. Small molecule inhibition of the menin-MLL interaction leads to loss of menin and MLL1 protein expression and to inhibition of growth and tumorigenicity...
April 19, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29672052/identification-of-selective-cell-active-inhibitors-of-protein-arginine-methyltransferase-5-prmt5-through-structure-based-virtual-screening-and-biological-assays
#20
Fei Ye, Weiyao Zhang, Xiaoqing Ye, Jia Jin, Zhengbing Lv, Cheng Luo
Protein arginine methyltransferase 5 (PRMT5), a type II PRMT enzyme, is reported as an important therapeutic target in leukemia and lymphoma. In the present study, based on the combination of virtual screening and biochemical validations, we discovered a series of small-molecule inhibitors targeting PRMT5. Among those, DC_Y134 exhibited the most potent activity with IC50 value of 1.7 μM and displayed good selectivity against other methyltransferases. Further treatment with DC_Y134 inhibited the proliferation of several hematological malignancy cell lines by causing cell cycle arrest and apoptosis...
April 19, 2018: Journal of Chemical Information and Modeling
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