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Chembiochem: a European Journal of Chemical Biology

Behnoosh Tajik-Ahmadabad, Adam Mechler, Benjamin W Muir, Keith McLean, Tracey M Hinton, Frances Separovic, Anastasios Polyzos
Biophysical studies were undertaken to investigate the binding and release of short interfering ribonucleic acid (siRNA) from lyotropic liquid crystalline lipid nanoparticles (LNPs) using a quartz crystal microbalance (QCM). These carriers are based on phytantriol (Phy) and a cationic lipid, DOTAP (1, 2-dioleoyl-3 trimethylammonium propane). The non-lamellar phase LNPs were tethered to the surface of the QCM chip for analysis based on biotin-neutravidin binding, which enabled the controlled deposition of siRNA-LNP complexes with different lipid/siRNA charge ratios on a QCM-D crystal sensor...
February 23, 2017: Chembiochem: a European Journal of Chemical Biology
Lijuan Pang, Matthew S Macauley, Britni M Arlian, Corwin M Nycholat, James C Paulson
Unwanted antibody responses significantly impact human health, and current options for treating deleterious antibody responses largely rely on broad immunosuppressants that can compromise overall immunity. A desirable alternative is to induce antigen-specific immune tolerance. We have shown that co-presentation of antigen and ligands of B cell Siglecs (sialic acid-binding immunoglobulin-like lectin) on a liposomal nanoparticle induces antigen-specific tolerance. Although Siglec-engaging tolerance-inducing antigenic liposomes (STALs) induce robust B cell tolerance in naïve mice, the full potential of STALs requires long-term tolerance induction and suppression of an ongoing immune response...
February 23, 2017: Chembiochem: a European Journal of Chemical Biology
Anna R Batt, Balyn W Zaro, Marisol X Navarro, Matthew Robert Pratt
Since the pioneering work by Reutter and co-workers that demonstrated structural flexibility in the carbohydrate biosynthesis and glycosylation pathways, many different labs have used unnatural monosaccharide analogs to perform glycan engineering on the surface of living cells. A subset of these unnatural monosaccharides contain bioorthogonal groups that enable the selective installation of visualization or enrichment tags. These metabolic chemical reporters (MCRs) have proven to be powerful for the unbiased identification of glycoproteins; however they do have certain limitations...
February 23, 2017: Chembiochem: a European Journal of Chemical Biology
Brenton Hammer, Yuzhou Wu, Stephan Fischer, Weina Liu, Tanja Weil, Klaus Müllen
Polyphenylene dendrimers (PPDs) represent a unique class of macromolecules based on their monodisperse and shape-persistent nature. These characteristics have enabled the synthesis of a new genre of "patched" surface dendrimers where their exterior can be functionalized with a variety of polar and unpolar substituents to yield lipophilic binding sites in a site-specific way. While such materials have proven capable of complexing biologically relevant molecules, shown high cellular uptake in various cell lines, and low to no toxicity; there is minimal understanding of the driving forces to these characteristics...
February 21, 2017: Chembiochem: a European Journal of Chemical Biology
Beatriz E Bolívar, John T Welch
Pyrazinamide (PZA), an essential constituent of short course tuberculosis chemotherapy, binds weakly but selectively to Sirtuin 6 (SIRT6). Despite structural similarities between nicotinamide (NAM), PZA, and pyrazinoic acid (POA), these inhibitors modulate SIRT6 via different mechanisms and binding sites, as suggested by Saturation Transfer Difference (STD) Nuclear Magnetic Resonance (NMR). Available experimental evidence, such as that derived from crystal structures and kinetic experiments, is of only limited utility in the elucidation of the mechanistic details of sirtuin inhibition by NAM or other inhibitors...
February 21, 2017: Chembiochem: a European Journal of Chemical Biology
Yizhou Li, Gunther Zimmermann, Jörg Scheuermann, Dario Neri
Phage-display libraries and DNA-encoded chemical libraries (DECL) represent useful tools for the isolation of specific binding molecules out of large combinatorial sets of compounds. In both methods, specific binders are recovered at the end of affinity capture procedures, using target proteins of interest immobilized on a solid support. However, while the efficiency of phage-display selections is routinely quantified by counting the phage titer before and after the affinity capture step, no similar quantification procedures have been reported for the characterization of DNA-encoded chemical library selections...
February 21, 2017: Chembiochem: a European Journal of Chemical Biology
Mohit Mathew, Elaine Tan, Jason W Labonte, Shivam Shah, Christopher T Saeui, Lingshu Liu, Rahul Bhattacharya, Patawut Bovonratwet, Jeffrey J Gray, Kevin Yarema
This report describes the metabolic glycoengineering (MGE) of intracellular esterase activity in human colon cancer (LS174T) and Chinese hamster ovary (CHO) cells. In silico analysis of the carboxylesterases CES1 and CES2 suggested that these enzymes are modified with sialylated N-glycans, which are proposed to stabilize the active multimeric forms of these enzymes. This premise was supported by treating cells with butanolylated ManNAc to increase sialylation, which in turn increased esterase activity. By contrast, hexosamine analogs not targeted to sialic acid biosynthesis (e...
February 20, 2017: Chembiochem: a European Journal of Chemical Biology
Andrea E Prota, Katja Bargsten, Mariano Redondo, Amos B Smith Iii, Chia-Ping H Yang, Hayley M McDaid, Ian Paterson, Susan B Horwitz, José Fernando Díaz, Michel O Steinmetz
Microtubule-stabilizing agents (MSAs) are widely used in chemotherapy. Here, using X-ray crystallography we describe the detailed binding modes of two potent MSAs, (+)-discodermolide (DDM) and the DDM-paclitaxel-hybrid KS-1-199-32, in the taxane pocket of ß-tubulin. Both compounds bind in a very similar hairpin conformation as previously observed in solution. However, they differentially stabilize the M-loop of ß-tubulin: KS-1-199-32 induces an M-loop helical conformation that is not observed for DDM. In the context of the microtubule structure, both MSAs connect the ß-tubulin helices H6 and H7 and loop S9-S10 with the M-loop, which is similar to the structural effects elicited by epothilone A, but distinct from paclitaxel...
February 16, 2017: Chembiochem: a European Journal of Chemical Biology
Tomohiro Higashino, Hirotaka Nakatsuji, Ryosuke Fukuda, Haruki Okamoto, Hirohiko Imai, Tetsuya Matsuda, Hidehito Tochio, Masahiro Shirakawa, Nikolai Tkachenko, Mitsuru Hashida, Tatsuya Murakami, Hiroshi Imahori
meso-Aryl substituted expanded porphyrins have two potential key features suitable for theranostic agents, excellent absorption in near infrared (NIR) region and possible introduction of multiple fluorine atoms at structurally nearly equivalent positions. Herein, hexaphyrin (hexa) was synthesized using 2,6-bis(trifluoromethyl)-4-formyl benzoate and pyrrole and evaluated as a novel theranostic expanded porphyrin possessing the above key features. Under NIR light illumination hexa showed intense photothermal and weak photodynamic effects, which were most likely due to its low-lying excited states close to a singlet oxygen...
February 15, 2017: Chembiochem: a European Journal of Chemical Biology
Jonas Hanske, Robert Wawrzinek, Andreas Geissner, Eike-Christian Wamhoff, Katrin Sellrie, Henrik Schmidt, Peter H Seeberger, Christoph Rademacher
The C-type lectin receptor Langerin is a glycan binding protein that serves as an uptake receptor on Langerhans cells and is essential for the formation of Birbeck granules. Whereas most of Langerin´s ligands are recognized via a canonical Ca2+-dependent binding site, interactions with heparins have been proposed to make additional contacts to a secondary, Ca2+-independent site. Glycan array screening and biomolecular NMR spectroscopy were employed to investigate the molecular mechanism of these interactions...
February 14, 2017: Chembiochem: a European Journal of Chemical Biology
Weili Zheng, Yi Lu, Shengchen Lin, Rui Wang, Lin Qiu, Yanlin Zhu, Benqiang Yao, Fusheng Guo, Shikai Jin, Lihua Jin, Yong Li
Farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce the conformational change of FXR that modulates its binding to coregulators, resulting in distinctive functional profiles of FXR. However, the mechanisms for selectively recruiting coregulators by FXR remain elusive, partly due to the lack of FXR selective modulators. We report here the identification of two natural terpenoids, tschimgine and feroline, as a novel class of FXR modulators. Remarkably, crystal structures uncover a secondary binding-induced pocket important for ligand binding...
February 10, 2017: Chembiochem: a European Journal of Chemical Biology
Flaviana Di Lorenzo, Alba Silipo, Lotte Bettina Andersen Gersby, Angelo Palmigiano, Rosa Lanzetta, Domenico Garozzo, Claudine Boyer, Olivier Pruvost, Mari-Anne Newman, Antonio Molinaro
Xanthomonas citri pv. citri is the pathogen responsible for the Asiatic citrus canker, one of the most serious diseases of citrus worldwide. The lipopolysaccharide (LPS) molecule was demonstrated to be involved in X. citri pv. citri virulence. Despite the enormous progress made in the investigation of molecular mechanisms responsible for bacterial pathogenicity, the determination of the detailed LPS structure-activity relationship still remains limited as the current knowledge is mainly based on structural determination of one X...
February 10, 2017: Chembiochem: a European Journal of Chemical Biology
Peng Xu, Meagan Kelly, Willie F Vann, Firdausi Qadri, Edward T Ryan, Paul Kovac
Using O-SP-core (O-SPcNH2) polysaccharide, isolated from Vibrio cholerae O1 lipopolysaccharide (LPS) and related synthetic substances, a detailed study of factors that affect conjugation of bacterial polysaccharides to protein carriers by squaric acid chemistry to form conjugate vaccines has been carried out. Several processes previously unrecognized, which take place during the squarate labelling of the O-SPcNH2 and subsequent conjugation of the squarate (O-SPcNH-SqOMe) formed, have been identified. The efficiency of conjugation at pH 8...
February 9, 2017: Chembiochem: a European Journal of Chemical Biology
Katrin Kestav, Kaido Viht, Anton Konovalov, Erki Enkvist, Asko Uri, Darja Lavogina
The atypical protein kinase Haspin serves as one of a key players in mitosis by catalysing phosphorylation of Thr3 in histone H3, and thus sustaining the normal functioning of the chromosomal passenger complex. Here, we report the development of bisubstrate-analogue inhibitors targeting Haspin. The compounds were constructed by linking 5-iodotubercidin moiety to the N-terminal sequence of histone H3. The new conjugates possessed high affinity (KD in the subnanomolar range) towards Haspin as well as slow kinetics of association and dissociation (residence time on the scale of several hours), which reflected their unique binding mode and translated into improved selectivity...
February 9, 2017: Chembiochem: a European Journal of Chemical Biology
Kanae Teruya, Gregory Rankin, Panagiotis Chrysanthopoulos, Kathryn Tonissen, Sally-Ann Poulsen
Chemical probes are small molecule reagents used by researchers for labeling and detection of biomolecules. We present the design, synthesis and characterisation of a panel of eleven structurally diverse photoaffinity labeling (PAL) probes as research tools for labeling the model enzyme carbonic anhydrase (CA) in challenging environments, including protein mixtures and cell lysates. We target ubiquitous CA II as well as the two cancer associated CAs (CA IX and CA XII), which are high priority as potential biomarkers of aggressive and/or multidrug resistant cancer...
February 8, 2017: Chembiochem: a European Journal of Chemical Biology
Nathan William Luedtke, Theodor Marsoner, Olivia Schmidt, Therese Trimer
The cationic porphyrin 5,10,15,20-tetrakis (diisopropyl-guanidine)-21H,23H-porphine "DIGPor" selectively binds to DNA containing O6-methylguanine (O6-MeG) and inhibits the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The O6-MeG selectivity and MGMT inhibitory activity of DIGPor was improved by incorporating ZnII into the porphyrin. The resulting metal complex "Zn-DIGPor" potentiated the activity of the DNA alkylating drug temozolomide in an MGMT-expressing cell line. To the best of our knowledge, these results provide the first examples of DNA-targeted MGMT inhibition...
February 8, 2017: Chembiochem: a European Journal of Chemical Biology
Nico Kress, Johanna Rapp, Bernhard Hauer
A deepened understanding of the > 99 % (S)-selective NCR ene reductase catalyzed reduction of both isomers of citral was generated by active site mutational studies and docking. Though structurally almost similar, the (E/Z)-isomers of citral showed a significantly varying selectivity response to introduced mutations. While it was possible to invert (E) citral reduction enantioselectivity to an e.e. of 46 % (R) by a W66A mutation, for (Z)-citral it remained ≥ 88 % (S) for all analyzed NCR single variants...
February 8, 2017: Chembiochem: a European Journal of Chemical Biology
Lena V Ivanova, Daniel Cibich, Gregory Deye, Marat R Talipov, Qadir Timerghazin
Nitroxyl HNO, a reduced form of an important gasotransmitter nitric oxide, exhibits its own unique biological activity. A possible biological pathway of HNO formation is S-thiolation reaction between thiols and S-nitrosothiols (RSNOs). Our DFT calculations suggests that S-thiolation proceeds through a proton transfer from thiol to the RSNO nitrogen atom, which increases electrophilicity of the RSNO sulfur, followed by nucleophilic attack by thiol yielding a charge-separated zwitterionic intermediate structure RSS+(R)N(H)O- (Zi), that decomposes yielding HNO and disulfide RSSR...
February 7, 2017: Chembiochem: a European Journal of Chemical Biology
Cyrille Grandjean, Johann Dion, Frédérique Deshayes, Nataliya Storozhylova, Tamara Advedissian, Annie Lambert, Mireille Viguier, Charles Tellier, Christophe Dussouy, Françoise Poirier
Galectins have been recognized as potential novel therapeutic targets in connection with the numerous fundamental biological processes which they are involved in. Galectins are key players of homeostasis and as such, their expression and function are finely tuned in vivo. As a consequence, their modes of action are complex and remain largely unexplored partly due the lack of dedicated tools. We thus thought to design galectin inhibitors from lactosamine core, functionalized at key C2 and C3' positions by aromatic subsituents to ensure both high affinity and selectivity, and equipped with a spacer which can be modified on demand to further modulate their intrinsic physico-chemical properties...
February 6, 2017: Chembiochem: a European Journal of Chemical Biology
Syed Shahzad-Ul-Hussan, Mallika Sastry, Thomas Lemmin, Cinque Soto, Sandra Loesgen, Danielle A Scott, Jack Robert Davison, Robert O'Connor, Peter D Kwong, Carole A Bewley
Man9GlcNAc2 (Man-9) present at the surface of HIV constitutes the binding sites of several HIV neutralizing agents and mammalian lectin DC-SIGN that is involved in cellular immunity and trans-infections. We describe the conformational properties of Man-9 in free state and when bound by an HIV entry inhibitor protein and define the minimum epitopes of two HIV binding proteins using NMR spectroscopy. In this regard we developed a robust expression system for production of 13C,15N-labeled glycans in mammalian cells that facilitated the implementation of 3D 13C-edited spectra to deconvolute spectral overlap allowing for the solution structure determination of Man-9...
February 6, 2017: Chembiochem: a European Journal of Chemical Biology
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