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Ligands and binding

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https://www.readbyqxmd.com/read/28103441/enantio-specific-allosteric-modulation-of-cannabinoid-1-receptor
#1
Robert B Laprairie, Pushkar M Kulkarni, Jeffrey R Deschamps, Melanie E M Kelly, David R Janero, Maria G Cascio, Lesley A Stevenson, Roger G Pertwee, Terry Kenakin, Eileen M Denovan-Wright, Ganesh A Thakur
The cannabinoid 1 receptor (CB1R) is one of the most widely expressed metabotropic G protein-coupled receptors in brain, and its participation in various (patho)physiological processes has made CB1R activation a viable therapeutic modality. Adverse psychotropic effects limit the clinical utility of CB1R orthosteric agonists and have promoted the search for CB1R positive allosteric modulators (PAMs) with the promise of improved drug-like pharmacology and enhanced safety over typical CB1R agonists. In this study, we describe the synthesis and in vitro and ex vivo pharmacology of the novel allosteric CB1R modulator GAT211 (racemic) and its resolved enantiomers, GAT228 (R) and GAT229 (S)...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28103425/efficient-synthesis-of-%C3%AE-galactosyl-oligosaccharides-using-a-mutant-bacteroides-thetaiotaomicron-retaining-%C3%AE-galactosidase-btgh97b
#2
Masayuki Okuyama, Kana Matsunaga, Ken-Ichi Watanabe, Keitaro Yamashita, Takayoshi Tagami, Asako Kikuchi, Min Ma, Patcharapa Klahan, Haruhide Mori, Min Yao, Atsuo Kimura
The preparation of a glycosynthase, a catalytic nucleophile mutant of a glycosidase, is a well-established strategy for the effective synthesis of glycosidic linkages. However, glycosynthases derived from α-glycosidases can give poor yields of desired products because they require generally unstable β-glycosyl fluoride donors. Here, we investigate a transglycosylation catalyzed by a catalytic nucleophile mutant derived from a glycoside hydrolase family (GH) 97 α-galactosidase, using more stable β-galactosyl azide and α-galactosyl fluoride donors...
January 19, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28103132/functional-gains-in-energy-and-cell-metabolism-after-tspo-gene-insertion
#3
Guo-Jun Liu, Ryan J Middleton, Winnie Wai-Ying Kam, David Y Chin, Claire R Hatty, Ronald H Y Chan, Richard B Banati
Recent loss-of-function studies in tissue-specific as well as global Tspo (Translocator Protein 18 kDa) knockout mice have not confirmed its long assumed indispensability for the translocation of cholesterol across the mitochondrial inter-membrane space, a rate-limiting step in steroid biosynthesis. Instead, recent studies in global Tspo knockout mice indicate that TSPO may play a more fundamental role in cellular bioenergetics, which may include the indirect down-stream regulation of transport or metabolic functions...
January 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28103033/design-synthesis-and-biological-evaluation-of-small-high-affinity-siglec-7-ligands-toward-novel-inhibitors-of-cancer-immune-evasion
#4
Horst Prescher, Martin Frank, Stephan Gütgemann, Elena Kuhfeldt, Astrid Schweizer, Lars Nitschke, Carsten Watzl, Reinhard Brossmer
Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion...
January 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28102740/update-on-functional-and-genetic-laboratory-assays-for-the-detection-of-platelet-microvesicles
#5
Maxime Laroche, Claire Dunois, Anne Marie Vissac, Jean Amiral
Functional and genetic assays for measuring platelet microvesicles (PMVs) are presented and discussed. Functional assays concern two groups of methods: a) homogeneous assays using the cofactor activity of phospholipids (PPLs) contained in PMVs and present in assayed plasmas, and a coagulation or a thrombin generation assay (TGA) as "end points"; b) capture-based assays, in which PMVs bind to an immobilized ligand, such as Annexin V in the presence of calcium, or monoclonal antibodies (MoAbs) specific for membrane proteins...
January 19, 2017: Platelets
https://www.readbyqxmd.com/read/28102676/novel-antitumor-platinum-ii-conjugates-containing-the-nonsteroidal-anti-inflammatory-agent-diclofenac-synthesis-and-dual-mechanisms-of-antiproliferative-effects
#6
Francesco Paolo Intini, Juraj Zajac, Vojtech Novohradsky, Teresa Saltarella, Concetta Pacifico, Viktor Brabec, Giovanni Natile, Jana Kasparkova
One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines...
January 19, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28102674/2d-ir-spectroscopy-shows-that-optimised-dna-minor-groove-binding-of-hoechst33258-follows-an-induced-fit-model
#7
Lennart A I Ramakers, Gordon Hithell, John J May, Gregory M Greetham, Paul M Donaldson, Michael Towrie, Anthony W Parker, Glenn A Burley, Neil T Hunt
The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced non-covalent interactions between ligand and biomolecule. Induced fit is well-established for small molecule-protein interactions, but its relevance to small molecule-DNA binding is less clear. We investigate the molecular determinants of Hoechst33258 binding to its preferred A-tract sequence relative to a sub-optimal alternating A-T sequence. Results from 2-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of minor groove spine of hydration in both sequences, but an additional perturbation of the base propeller twists occurs in the A-tract binding region...
January 19, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28102507/-44-sc-psma-617-for-radiotheragnostics-in-tandem-with-177-lu-psma-617-preclinical-investigations-in-comparison-with-68-ga-psma-11-and-68-ga-psma-617
#8
Christoph A Umbricht, Martina Benešová, Raffaella M Schmid, Andreas Türler, Roger Schibli, Nicholas P van der Meulen, Cristina Müller
BACKGROUND: The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging ((68)Ga) and radionuclide therapy ((177)Lu) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced (44)Sc (T 1/2 = 4...
December 2017: EJNMMI Research
https://www.readbyqxmd.com/read/28102121/inflammasomes-in-myeloid-cells-warriors-within
#9
Sushmita Jha, W June Brickey, Jenny Pan-Yun Ting
The inflammasome is a large multimeric protein complex comprising an effector protein that demonstrates specificity for a variety of activators or ligands; an adaptor molecule; and procaspase-1, which is converted to caspase-1 upon inflammasome activation. Inflammasomes are expressed primarily by myeloid cells and are located within the cell. The macromolecular inflammasome structure can be visualized by cryo-electron microscopy. This complex has been found to play a role in a variety of disease models in mice, and several have been genetically linked to human diseases...
January 2017: Microbiology Spectrum
https://www.readbyqxmd.com/read/28101696/role-of-the-helix-in-talin-f3-domain-f3-helix-in-talin-mediated-integrin-activation
#10
Ang Li, Qiang Guo, Ailin Wei, Yaliang Zhou, Weiming Hu
Increases in ligand binding to cellular integrins (activation) play an important role in platelet and leukocyte function. Talin is necessary in vivo and sufficient in vitro for integrin αIIbβ3 activation. The precise mechanisms by which talin activates integrin are still being elucidated. In particular, talin undergoes conformational changes (around the F3 helix) and inserts the F3 helix into lipid bilayer; however, the connection between this lipid-inserting mechanism of talin and talin's capacity to activate integrin has never been explored before...
January 18, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28101682/synthesis-spectral-and-extended-spectrum-beta-lactamase-studies-of-transition-metal-tetraaza-macrocyclic-complexes
#11
Dinesh Kumar, Nutan Sharma, Manjula Nair
Urinary tract infections commonly occur in humans due to microbial pathogens invading the urinary tract, which can bring about a range of clinical symptoms and potentially fatal sequelae. The present study is aimed at addressing the development of a new antimicrobial agent against extended spectrum beta lactamase (ESBL) producing E. coli bacteria. We have synthesised some biologically potent (NNNN) donor macrocycles (L 1  = dibenzo[f,n]dipyrido[3,4-b:4',3'-j][1,4,9,12]tetraazacyclohexadecine-6,11,18,23(5H,12H, 7H, 24H)-tetraone, and L 2  = 6,12,19,25-tetraoxo-4,6,11,12,16,18,23,24-octahydrotetrabenzo [b,g,k,p][1,5,10,14]tetra azacyclooctadecine-2,13-dicarboxylic acid) and their Ti and Zr metal complexes in alcoholic media using microwave protocol...
January 18, 2017: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/28101207/structure-function-analysis-of-dna-helicase-helq-a-new-diagnostic-marker-in-ovarian-cancer
#12
Ya-Ping Li, Jun-Juan Yang, Hui Xu, En-Yu Guo, Yan Yu
It has been previously reported that a deficiency of the helicase, POLQ-like (HELQ) gene increases the risk of ovarian cancer. The present study aimed to explore the structure-function association of HELQ and discuss the effect of molecular structure on the occurrence of tumors. ExPASy tools were employed to analyze the physicochemical properties and secondary structure of the genes. PHYRE2 Protein Fold Recognition Server was used to construct the three-dimensional model and find the ligand-binding sites of HELQ...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28100911/variants-on-chromosome-4q21-near-pkd2-and-siblings-are-associated-with-dental-caries
#13
Scott Eckert, Eleanor Feingold, Margaret Cooper, Michael M Vanyukov, Brion S Maher, Rebecca L Slayton, Marcia C Willing, Steven E Reis, Daniel W McNeil, Richard J Crout, Robert J Weyant, Steven M Levy, Alexandre R Vieira, Mary L Marazita, John R Shaffer
A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus...
January 19, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28100839/tyrosine-kinase-blocking-collagen-iv-derived-peptide-suppresses-ocular-neovascularization-and-vascular-leakage
#14
Raquel Lima E Silva, Yogita Kanan, Adam C Mirando, Jayoung Kim, Ron B Shmueli, Valeria E Lorenc, Seth D Fortmann, Jason Sciamanna, Niranjan B Pandey, Jordan J Green, Aleksander S Popel, Peter A Campochiaro
Vascular endothelial growth factor (VEGF)-neutralizing proteins provide benefit in several retinal and choroidal vascular diseases, but some patients still experience suboptimal outcomes, and the need for frequent intraocular injections is a barrier to good outcomes. A mimetic peptide derived from collagen IV, AXT107, suppressed subretinal neovascularization (NV) in two mouse models predictive of effects in neovascular age-related macular degeneration (NVAMD) and inhibited retinal NV in a model predictive of effects in ischemic retinopathies...
January 18, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28100773/targeted-fc%C3%AE-r-mediated-clearance-by-a-biparatopic-bispecific-antibody
#15
Srinath Kasturirangan, G Jonah Rainey, Linda Xu, Xinwei Wang, Alyse Portnoff, Tracy Chen, Christine Fazenbaker, Helen Zhong, Jared Bee, Zhutian Zeng, Craig Jenne, Herren Wu, Changshou Gao
Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. While monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6 mediated signaling...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28100749/promoted-interaction-of-c-ebp%C3%AE-with-demethylated-cxcr3-gene-promoter-contributes-to-neuropathic-pain-in-mice
#16
Bao-Chun Jiang, Li-Na He, Xiao-Bo Wu, Hui Shi, Wen-Wen Zhang, Zhi-Jun Zhang, De-Li Cao, Chun-Hua Li, Jun Gu, Yong-Jing Gao
: DNA methylation has been implicated in the pathogenesis of chronic pain. However, the specific genes regulated by DNA methylation under neuropathic pain condition remain largely unknown. Here we investigated how chemokine receptor CXCR3 is regulated by DNA methylation and how it contributes to neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased Cxcr3 mRNA and protein expression in the neurons of the spinal cord. Meanwhile, the CpG (5'-cytosine-phosphate-guanine-3') island in the Cxcr3 gene promoter region was demethylated, and the expression of DNA methyltransferase 3b (DNMT3b) was decreased...
January 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28100681/lfa-1-activation-in-nk-cells-and-their-subsets-influence-of-receptors-maturation-and-cytokine-stimulation
#17
Doris Urlaub, Kristine Höfer, Martha-Lena Müller, Carsten Watzl
The integrin LFA-1 is essential for efficient activation and for cytotoxicity of NK cells because it initiates the assembly of the immunological synapse and mediates firm adhesion to the target. LFA-1 is also needed to polarize the cytotoxic machinery of the NK cell toward the target cell. The binding affinity and avidity of integrins can be regulated via inside-out signals from other receptors. In this article, we investigate the signals necessary to activate LFA-1 in human NK cells. Our data show that LFA-1 has a low ligand-binding activity in resting human NK cells, but it can be stimulated by triggering activating receptors, such as 2B4 or CD16, or by coactivation of different receptor combinations...
January 18, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28100677/paired-siglec-receptors-generate-opposite-inflammatory-responses-to-a-human-specific-pathogen
#18
Flavio Schwarz, Corinna S Landig, Shoib Siddiqui, Ismael Secundino, Joshua Olson, Nissi Varki, Victor Nizet, Ajit Varki
Paired immune receptors display near-identical extracellular ligand-binding regions but have intracellular sequences with opposing signaling functions. While inhibitory receptors dampen cellular activation by recognizing self-associated molecules, the functions of activating counterparts are less clear. Here, we studied the inhibitory receptor Siglec-11 that shows uniquely human expression in brain microglia and engages endogenous polysialic acid to suppress inflammation. We demonstrated that the human-specific pathogen Escherichia coli K1 uses its polysialic acid capsule as a molecular mimic to engage Siglec-11 and escape killing...
January 18, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28100627/inflammatory-biomarkers-predict-heart-failure-severity-and-prognosis-in-patients-with-heart-failure-with-preserved-ejection-fraction-a-holistic-proteomic-approach
#19
Camilla Hage, Erik Michaëlsson, Cecilia Linde, Erwan Donal, Jean-Claude Daubert, Li-Ming Gan, Lars H Lund
BACKGROUND: Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. METHODS AND RESULTS: In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay...
February 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/28100151/renin-inhibition-by-soyasaponin-i-a-potent-native-anti-hypertensive-compound
#20
Zeinab Tavassoli, Majid Taghdir, Bijan Ranjbar
One way to control hypertension is inactivation of the Renin- Angiotensin- Aldosterone System (RAAS). Inhibition of renin as a rate-limiting step of this system is an effective way to stop up RAAS. It has been proved that soyasaponin I, an herbal compound obtained from soybeans, has anti-hypertensive effect via renin inhibition, so it has the potential of being an anti-hypertensive drug. Herein, some theoretical approaches such as Docking Simulation, Molecular Dynamics (MD) Simulation and MMPBSA analysis have been used to study how soyasaponin I inhibits renin at the structural level...
January 19, 2017: Journal of Biomolecular Structure & Dynamics
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