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https://www.readbyqxmd.com/read/29346724/structural-and-biophysical-characterization-of-human-extl3-domain-organisation-glycosylation-and-solution-structure
#1
Wael Awad, Sven Kjellstrom, Gabriel Svensson Birkedal, Katrin Mani, Derek Thomas Logan
Heparan sulfate proteoglycans are proteins substituted with one or more heparan sulfate (HS) polysaccharides, found in abundance at cell surfaces. HS chains influence the activity of many biologically important molecules involved in cellular communication and signaling. The exostosin (EXT) proteins are glycosyltransferases in the Golgi apparatus that assemble HS chains on HSPGs. The EXTL3 enzyme mainly works as an initiator in HS biosynthesis. In this work, human lumenal N-glycosylated EXTL3 (EXTL3ΔN) was cloned, expressed in human embryonic kidney cells and purified...
January 18, 2018: Biochemistry
https://www.readbyqxmd.com/read/29346275/a-review-on-recent-advances-in-stabilizing-peptides-proteins-upon-fabrication-in-hydrogels-from-biodegradable-polymers
#2
REVIEW
Faisal Raza, Hajra Zafar, Ying Zhu, Yuan Ren, Aftab -Ullah, Asif Ullah Khan, Xinyi He, Han Han, Md Aquib, Kofi Oti Boakye-Yiadom, Liang Ge
Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to overcome the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. The aqueous swellable and crosslinked polymeric network structure of hydrogels is composed of various natural, synthetic and semisynthetic biodegradable polymers. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility. All these dynamic properties of hydrogels have increased the interest in their use as a carrier for peptides and proteins to be released slowly in a sustained manner...
January 18, 2018: Pharmaceutics
https://www.readbyqxmd.com/read/29344895/bioinformatics-approaches-to-predict-drug-responses-from-genomic-sequencing
#3
Neel S Madhukar, Olivier Elemento
Fulfilling the promises of precision medicine will depend on our ability to create patient-specific treatment regimens. Therefore, being able to translate genomic sequencing into predicting how a patient will respond to a given drug is critical. In this chapter, we review common bioinformatics approaches that aim to use sequencing data to predict sample-specific drug susceptibility. First, we explain the importance of customized drug regimens to the future of medical care. Second, we discuss the different public databases and community efforts that can be leveraged to develop new methods for identifying new predictive biomarkers...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29343613/restricted-hiv-1-env-glycan-engagement-by-lectin-reengineered-davei-protein-chimera-is-sufficient-for-lytic-inactivation-of-the-virus
#4
Bibek Parajuli, Kriti Acharya, Harry C Bach, Bijay Parajuli, Shiyu Zhang, Amos B Smith, Cameron F Abrams, Irwin Chaiken
We previously reported first generation recombinant DAVEI construct, a dual action virus entry inhibitor composed of cyanovirin-N (CVN) fused to a membrane proximal external region (MPER) or its derivative peptide Trp3. DAVEI exhibits potent and irreversible inactivation of HIV-1 viruses by dual engagement of gp120 and gp41. However, the promiscuity of CVN to associate with multiple glycosylation sites in gp120 and its multivalency limit current understanding of the molecular arrangement of the DAVEI molecules on trimeric spike...
January 17, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29342447/design-synthesis-and-anticancer-studies-of-novel-aminobenzazolyl-pyrimidines-as-tyrosine-kinase-inhibitors
#5
Rupesh Chikhale, Sonali Thorat, Rajan Kumar Choudhary, Nikhil Gadewal, Pramod Khedekar
Abnormal signalling from the Protein tyrosine kinases (PTKs) like receptor tyrosine kinases and intracellular tyrosine kinases can lead to diseases such as cancer especially non-small cell lung cancer, chronic myeloid leukaemia and gastrointestinal stromal tumours. Various Protein tyrosine kinase inhibitors are available but face poor bioavailability, severe toxicities and recent cases of drug-resistant cancers prompts for development of better drug molecules. In this study we report the design and development of a novel Protein Tyrosine Kinase (PTK) inhibitor on the basis of pharmacophore modelling...
January 4, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29342416/identification-of-novel-quinazolinedione-derivatives-as-ror%C3%AE-t-inverse-agonist
#6
Yoshiyuki Fukase, Ayumu Sato, Yoshihide Tomata, Atsuko Ochida, Mitsunori Kono, Kazuko Yonemori, Keiko Koga, Toshitake Okui, Masashi Yamasaki, Yasushi Fujitani, Hideyuki Nakagawa, Ryoukichi Koyama, Masaharu Nakayama, Robert Skene, Bi-Ching Sang, Isaac Hoffman, Junya Shirai, Satoshi Yamamoto
Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity...
December 28, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29339213/nrp-2-in-tumor-lymphangiogenesis-and-lymphatic-metastasis
#7
Jingwen Wang, Yuhong Huang, Jun Zhang, Boyi Xing, Wei Xuan, Honghai Wang, He Huang, Jiayu Yang, Jianwu Tang
Neuropilin-2 (NRP-2) not only functions as a receptor for semaphorins, a family of neural axon guidance factors, but also interacts with VEGFs, a family of vascular endothelial growth factors. As an independent receptor or a co-receptor, NRP-2 binds to ligands VEGF-C/D, activates the VEGF-C/D-NRP-2 signaling axis, and further regulates lymphangiogenesis-associated factors in both lymphatic endothelial cells (LECs) and some tumor cells during tumor progression. Via VEGF-C/D-NRP-2 axis, NRP-2 induces LEC proliferation, reconstruction and lymphangiogenesis and subsequently promotes tumor cell migration, invasion and lymphatic metastasis...
January 12, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29339152/biogenic-triamine-and-tetraamine-activate-core-catalytic-ability-of-tetrahymena-group-i-ribozyme-in-the-absence-of-its-large-activator-module
#8
Mst Ara Gulshan, Md Motiar Rahman, Shigeyoshi Matsumura, Tsunehiko Higuchi, Naoki Umezawa, Yoshiya Ikawa
Group I intron ribozymes share common core elements that form a three-dimensional structure responsible for their catalytic activity. This core structure is unstable without assistance from additional factors that stabilize its tertiary structure. We examined biogenic triamine and tetraamine and also their fragments for their abilities to stabilize a structurally unstable group I ribozyme, ΔP5 ribozyme, derived from the Tetrahymena group I intron ribozyme by deleting its large activator module. Biogenic triamine (spermidine) and tetraamine (spermine) efficiently activated the ΔP5 ribozyme under conditions where the ribozyme was virtually inactive...
January 12, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29338975/critical-effects-of-polar-fluorescent-probes-on-the-interaction-of-dha-with-popc-supported-lipid-bilayers
#9
Kiera R Flynn, Alessandra Sutti, Lisandra L Martin, M Leigh Ackland, Angel A J Torriero
The understanding of lipid bilayer structure and function has been advanced by the application of molecular fluorophores. However, the effects of these probe molecules on the physicochemical properties of membranes being studied are poorly understood. A quartz crystal microbalance with dissipation monitoring instrument was used in this work to investigate the impact of two commonly used fluorescent probes, 1-palmitoyl-2-{12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl}-sn-glycero-3-phosphocholine (NBD-PC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine-B-sulfonyl) (Lis-Rhod PE), on the formation and physicochemical properties of a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine supported lipid bilayer (POPC-SLB)...
January 12, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29337418/specific-non-covalent-interactions-determine-optimal-structure-of-a-buried-ligand-moiety-qm-mm-and-pure-qm-modeling-of-complexes-of-the-small-molecule-cd4-mimetics-and-hiv1-gp120
#10
Francesca Moraca, David Rinaldo, Amos Brittain Smith, Cameron Abrams
The small molecule CD4 mimetics (smCD4mc) are a class of highly potent HIV-1 entry inhibitors characterized by a unique SAR. They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, so-called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all lead to loss of activity, despite they are predicted to bind equally well via standard empirical computational approaches making difficult to further optimize this region of the compounds to increase binding to gp120...
January 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29337202/progress-with-covalent-small-molecule-kinase-inhibitors
#11
REVIEW
Zheng Zhao, Philip E Bourne
With reduced risk of toxicity and high selectivity, covalent small-molecule kinase inhibitors (CSKIs) have emerged rapidly. Through the lens of structural system pharmacology, here we review this rapid progress by considering design strategies and the challenges and opportunities offered by current CSKIs.
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337067/the-impact-of-growth-factors-on-human-induced-pluripotent-stem-cells-differentiation-into-cardiomyocytes
#12
Marianne E Yassa, Iman A Mansour, Nadia I Sewelam, Hala Hamza, Taghrid Gaafar
Human induced pluripotent stem cells (hiPSCs) act as a promising therapeutic alternative for cardiovascular diseases. They yield a large number of functional cardiomyocytes (CMs) from autologous cell sources without ethical or immunological problems. However, significant limitations still remain in terms of line-to-line variability in CM yield and reproducibility. AIM: To efficiently enhance NP0040 hiPSCs differentiation into CMs. MAIN METHODS: Following a standard cardiac differentiation protocol using small molecules targeting the canonical Wnt signaling, growth factors (BMP4 and FGF2) and ascorbic acid were added further in order to increase the cardiac differentiation efficiency...
January 11, 2018: Life Sciences
https://www.readbyqxmd.com/read/29337052/sweet-yet-underappreciated-proteoglycans-and-extracellular-matrix-remodeling-in-heart-disease
#13
REVIEW
Geir Christensen, Kate M Herum, Ida G Lunde
Extracellular matrix remodeling is extensive in several heart diseases and hampers cardiac filling, often leading to heart failure. Proteoglycans have over the last two decades emerged as molecules with important roles in matrix remodeling and fibrosis in the heart. Here we discuss and review current literature on proteoglycans that have been studied in cardiac remodeling. The small leucine rich proteoglycans (SLRPs) are located within the extracellular matrix and are organizers of the matrix structure. Membrane-bound proteoglycans, such as syndecans and glypicans, act as receptors and direct cardiac fibroblast signaling...
January 11, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29336951/design-synthesis-and-evaluation-against-chikungunya-virus-of-novel-small-molecule-antiviral-agents
#14
Roberta Tardugno, Gilda Giancotti, Tine De Burghgraeve, Leen Delang, Johan Neyts, Pieter Leyssen, Andrea Brancale, Marcella Bassetto
Chikungunya virus is a re-emerging arbovirus transmitted to humans by mosquitoes, responsible for an acute flu-like illness associated with debilitating arthralgia, which can persist for several months or become chronic. In recent years, this viral infection has spread worldwide with a previously unknown virulence. To date, no specific antivirals treatments nor vaccines are available against this important pathogen. Starting from the structures of two antiviral hits previously identified in our research group with in silico techniques, this work describes the design and preparation of 31 novel structural analogues, with which different pharmacophoric features of the two hits have been explored and correlated with the inhibition of Chikungunya virus replication in cells...
January 6, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29336885/structural-basis-for-activity-and-specificity-of-an-anticoagulant-anti-fxia-monoclonal-antibody-and-a-reversal-agent
#15
Lauren K Ely, Marco Lolicato, Tovo David, Kate Lowe, Yun Cheol Kim, Dharmaraj Samuel, Paul Bessette, Jorge L Garcia, Thomas Mikita, Daniel L Minor, Shaun R Coughlin
Coagulation factor XIa is a candidate target for anticoagulants that better separate antithrombotic efficacy from bleeding risk. We report a co-crystal structure of the FXIa protease domain with DEF, a human monoclonal antibody that blocks FXIa function and prevents thrombosis in animal models without detectable increased bleeding. The light chain of DEF occludes the FXIa S1 subsite and active site, while the heavy chain provides electrostatic interactions with the surface of FXIa. The structure accounts for the specificity of DEF for FXIa over its zymogen and related proteases, its active-site-dependent binding, and its ability to inhibit substrate cleavage...
January 2, 2018: Structure
https://www.readbyqxmd.com/read/29336146/coordination-triggered-hierarchical-folate-zinc-supramolecular-hydrogels-leading-to-printable-biomaterials
#16
Kaerdun Liu, Shihao Zang, Rongrong Xue, Jinghui Yang, Lizhi Wang, Jianbin Huang, Yun Yan
Printable hydrogels desired in bioengineering have extremely high demands on biocompatibility and mechanic strength, which can hardly be achieved in conventional hydrogels made with biopolymers. Here we show that on employment of the strategy of coordination triggered hierarchical self-assembly of naturally occurred small molecule folic acid, supramolecular hydrogels with robust mechanical elastic modulus comparable to synthetic double network (DN) polymer gels can be made at concentrations below 1 %. A sequence of hierarchical steps are involved in the formation of this extraordinary hydrogel: petrin rings on folate form tetramers through hydrogen bonding, tetramers stack into nanofibers by π-π stacking, zinc ions cross-link the nanofibers into larger scale fibrils, and further crosslink the fibril network to gel water...
January 16, 2018: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29334896/global-analysis-of-prokaryotic-trna-derived-cyclodipeptide-biosynthesis
#17
Michael A Skinnider, Chad W Johnston, Nishanth J Merwin, Chris A Dejong, Nathan A Magarvey
BACKGROUND: Among naturally occurring small molecules, tRNA-derived cyclodipeptides are a class that have attracted attention for their diverse and desirable biological activities. However, no tools are available to link cyclodipeptide synthases identified within prokaryotic genome sequences to their chemical products. Consequently, it is unclear how many genetically encoded cyclodipeptides represent novel products, and which producing organisms should be targeted for discovery. RESULTS: We developed a pipeline for identification and classification of cyclodipeptide biosynthetic gene clusters and prediction of aminoacyl-tRNA substrates and complete chemical structures...
January 15, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29334736/hydration-behavior-along-the-folding-pathways-of-trpzip4-trpzip5-and-trpzip6
#18
Madhulika Gupta, Prabir Khatua, Charusita Chakravarty, Sanjoy Bandyopadhyay
The microscopic properties of water confined within different segments of Trpzip4 (TZ4), Trpzip5 (TZ5) and Trzpip6 (TZ6) have been compared for all the states characterized along their folding pathways. In particular, structural ordering, energetics, and dynamics of water have been examined as the peptide unfolds along the free energy landscape. It is observed that the structuring of tetrahedral network as well as translational and rotational motions of hydration waters confined within the strands and the turn regions are very different, revealing motional heterogeneity in small 16-residue trpzips...
January 15, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29334380/light-activated-chemical-probing-of-nucleobase-solvent-accessibility-inside-cells
#19
Chao Feng, Dalen Chan, Jojo Joseph, Mikko Muuronen, William H Coldren, Nan Dai, Ivan R Corrêa, Filipp Furche, Christopher M Hadad, Robert C Spitale
The discovery of functional RNAs that are critical for normal and disease physiology continues to expand at a breakneck pace. Many RNA functions are controlled by the formation of specific structures, and an understanding of each structural component is necessary to elucidate its function. Measuring solvent accessibility intracellularly with experimental ease is an unmet need in the field. Here, we present a novel method for probing nucleobase solvent accessibility, Light Activated Structural Examination of RNA (LASER)...
January 15, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29334220/computational-design-synthesis-and-structure-property-evaluation-of-1-3-thiazole-based-colour-tunable-multiheterocyclic-small-organic-fluorophores-as-multifunctional-molecular-materials
#20
Rakesh Radhakrishnan, Kumaran G Sreejalekshmi
Probing chemical space of luminescent organic materials built on novel cores is highly imperative for its potential to expand the horizons of advanced functional materials. Small organic fluorophores possessing therapeutic traits can contribute to theranostics. We coupled computational and classical synthetic chemistry strategies for the rational design of 5-(hetero-2-yl)-1,3-thiazoles as colour tunable fluorophore core. With the aid of DFT and TD-DFT, we prove multiheterocyclic system built on thiazole-het core with three inherent tunable sites on thiazole (C2, C4 and C5) capable of accommodating panoply of substituents, as a multifunctional molecular materials' platform...
January 15, 2018: Journal of Organic Chemistry
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