Read by QxMD icon Read

ACS Chemical Biology

Keun Ah Ryu, Katarzyna Slowinska, Troy Moore, Aaron Esser-Kahn
We report immune response modulation with linked Toll-like receptor (TLR) agonists. Conjugating two agonists of synergistic TLRs induce an increase in immune activity compared to equal molarity of soluble agonists. Additionally, varying the distance between the agonists by changing the linker length alters the level of macrophage NF-κB activity as well as primary bone marrow derived dendritic cell IL-6 production. This modulation is effected by the size of the agonists and the pairing of the stimulated TLRs...
October 17, 2016: ACS Chemical Biology
Sang Joon Won, Dahvid Davda, Kristin J Labby, Sin Ye Hwang, Rachel E Pricer, Jaimeen D Majmudar, Kira A Armacost, Laura A Rodriguez, Christina L Rodriguez, Fei San Chong, Kristopher A Torossian, Jasmine Palakurthi, Edward S Hur, Jennifer L Meagher, Charles L Brooks, Jeanne A Stuckey, Brent R Martin
Post-translational S-palmitoylation directs the trafficking and membrane localization of hundreds of cellular proteins, often involving a coordinated palmitoylation cycle that requires both protein acyl transferases (PATs) and acyl protein thioesterases (APTs) to actively re-distribute S-palmitoylated proteins towards different cellular membrane compartments. This process is necessary for the trafficking and oncogenic signaling of S-palmitoylated Ras isoforms, and potentially other peripheral membrane proteins...
October 17, 2016: ACS Chemical Biology
Arne H Smits, Annika Borrmann, Mark Roosjen, Jan C M van Hest, Michiel Vermeulen
Epitope-tagging is an effective tool to facilitate protein enrichment from crude cell extracts. Traditionally, N- or C-terminal fused tags are employed, which, however, can perturb protein function. Unnatural amino acids (UAAs) harboring small reactive handles can be site-specifically incorporated into proteins, thus serving as a potential alternative for conventional protein tags. Here, we introduce Click-MS, which combines the power of site-specific UAA incorporation, bioorthogonal chemistry, and quantitative mass spectrometry-based proteomics to specifically enrich a single protein of interest from crude mammalian cell extracts...
October 17, 2016: ACS Chemical Biology
Anju Singh, Sreedhar Venkannagari, Kyu H Oh, Ya-Qin Zhang, Jason M Rohde, Li Liu, Sridhar Nimmagadda, Kuladeep Sudini, Kyle R Brimacombe, Sachin Gajghate, Jinfang Ma, Amy Wang, Xin Xu, Sampada A Shahane, Menghang Xia, Juhyung Woo, George A Mensah, Zhibin Wang, Marc Ferrer, Edward Gabrielson, Zhuyin Li, Fraydoon Rastinejad, Min Shen, Matthew B Boxer, Shyam Biswal
Loss of function mutations in Kelch-like ECH Associated Protein 1 (KEAP1), or gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (NRF2), are common in non-small cell lung cancer (NSCLC) and associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughput screen using a diverse set of ∼400 000 small molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the National Center for Advancing Translational Sciences...
October 17, 2016: ACS Chemical Biology
Kalie Ann Mix, Matthew R Aronoff, Ronald T Raines
Diazo groups have broad and tunable reactivity. That and other attributes endow diazo compounds with the potential to be valuable reagents for chemical biologists. The presence of diazo groups in natural products underscores their metabolic stability and anticipates their utility in a biological context. The chemoselectivity of diazo groups, even in the presence of azido groups, presents many opportunities. Already, diazo compounds have served as chemical probes and elicited novel modifications of proteins and nucleic acids...
October 14, 2016: ACS Chemical Biology
Jing Li, Jiajia Wang, Liuqing Wen, He Zhu, Shanshan Li, Kenneth Huang, Kuan Jiang, Xu Li, Cheng Ma, Jingyao Qu, Aishwarya Parameswaran, Jing Song, Wei Zhao, Peng George Wang
O-linked β-N-acetyl-glucosamine (O-GlcNAc) is an essential and ubiquitous post-translational modification present in nucleic and cytoplasmic proteins of multicellular eukaryotes. The metabolic chemical probes such as GlcNAc or GalNAc analogues bearing ketone or azide handles, in conjunction with bioorthogonal reactions, provide a powerful approach for detecting and identifying this modification. However, these chemical probes either enter multiple glycosylation pathways or have low labeling efficiency. Therefore, selective and potent probes are needed to assess this modification...
October 14, 2016: ACS Chemical Biology
Phi Doan, Demar R G Pitter, Andrea Kocher, James N Wilson, Theodore Goodson
The classical model for DNA groove binding states that groove binding molecules should adopt a crescent shape that closely matches the helical groove of DNA. Here, we present a new design strategy that does not obey this classical model. The DNA-binding mechanism of small organic molecules was investigated by synthesizing and examining a series of novel compounds that bind with DNA. This study has led to the emergence of structure-property relationships for DNA-binding molecules and/or drugs, which reveals that the structure can be designed to either intercalate or groove bind with calf thymus dsDNA by modifying the electron acceptor properties of the central heterocyclic core...
October 13, 2016: ACS Chemical Biology
Dominic I James, Kate M Smith, Allan M Jordan, Emma E Fairweather, Louise A Griffiths, Nicola S Hamilton, James R Hitchin, Colin P Hutton, Stuart Jones, Paul Kelly, Alison E McGonagle, Helen Small, Alexandra I J Stowell, Julie Tucker, Ian D Waddell, Bohdan Waszkowycz, Donald J Ogilvie
The enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, a detailed understanding of its mechanism of action has been hampered by a lack of credible, cell-active chemical probes. Herein, we demonstrate inhibition of PARG with a small molecule, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells. Moreover, we describe two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity...
October 12, 2016: ACS Chemical Biology
Pavithra M Dedigama-Arachchige, Mary Kay H Pflum
Few methods are available to discover the cellular kinase that phosphorylates a specific amino acid, or phosphosite, on a protein. In addition, identifying the associated proteins bound near a phosphosite during phosphorylation would provide insights into cell biology and signaling. Here we report K-CLASP (Kinase Catalyzed CrossLinking And Streptavidin Purification) as a method for both phosphosite-specific kinase identification and the discovery of kinase interacting proteins. K-CLASP offers a powerful tool to discover unanticipated protein-protein interactions in phosphorylation-mediated biological events...
October 11, 2016: ACS Chemical Biology
Meredith A Skiba, Andrew P Sikkema, William D Fiers, William H Gerwick, David H Sherman, Courtney C Aldrich, Janet L Smith
Polyketide metabolites produced by modular type I polyketide synthases (PKS) acquire their chemical diversity through the variety of catalytic domains within modules of the pathway. Methyltransferases are among the least characterized of the catalytic domains common to PKS systems. We determined the domain boundaries and characterized the activity of a PKS C-methyltransferase (C-MT) from the curacin A biosynthetic pathway. The C-MT catalyzes S-adenosylmethionine-dependent methyl transfer to the α-position of β-ketoacyl substrates linked to acyl carrier protein (ACP) or a small-molecule analog, but does not act on β-hydroxyacyl substrates or malonyl-ACP...
October 10, 2016: ACS Chemical Biology
Ivone M Martins, Rui L Reis, Helena S Azevedo
The field of regenerative medicine has been gaining momentum steadily over the past few years. The emphasis in regenerative medicine is to use various in vitro and in vivo approaches that leverage the intrinsic healing mechanisms of the body to treat patients with disabling injuries and chronic diseases such as diabetes, osteoarthritis, and degenerative disorders of the cardiovascular and central nervous system. Phage display has been successfully employed to identify peptide ligands for a wide variety of targets, ranging from relatively small molecules (enzymes, cell receptors) to inorganic, organic, and biological (tissues) materials...
October 10, 2016: ACS Chemical Biology
Ken Yamada, Ji-Hu Zhang, Xiaoling Xie, Juergen Reinhardt, Amy Qiongshu Xie, Daniel LaSala, Darcy Kohls, David Yowe, Debra Burdick, Hajime Yoshisue, Hiromichi Wakai, Isabel Schmidt, Jason Gunawan, Kayo Yasoshima, Q Kimberley Yue, Mitsunori Kato, Muneto Mogi, Neeraja Idamakanti, Natasha Kreder, Peter Drueckes, Pramod Pandey, Toshio Kawanami, Waanjeng Huang, Yukiko I Yagi, Zhan Deng, Hyi-Man Park
Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration and/or stringent hit triaging with high ATP concentration offer conceptually simple methods of identifying allosteric inhibitors...
October 7, 2016: ACS Chemical Biology
Colin R Andrew, Olga N Petrova, Isabelle Lamarre, Jean-Christophe Lambry, Fabrice Rappaport, Michel Negrerie
Nitric oxide (NO) sensors are heme proteins which may also bind CO and O2. Control of heme-gas affinity and their discrimination are achieved by the structural properties and reactivity of the heme and its distal and proximal environments, leading to several energy barriers. In the bacterial NO-sensor cytochrome c' from Alcaligenes xylosoxidans (AXCP), the single Leu16Ala distal mutation boosts the affinity for gas ligands by a remarkable 106-108-fold, transforming AXCP from one of the lowest affinity gas binding proteins to one of the highest...
October 6, 2016: ACS Chemical Biology
Ewa Surmiak, Aleksandra Twarda-Clapa, Krzysztof M Zak, Bogdan Musielak, Marcin D Tomala, Katarzyna Kubica, Przemysław Grudnik, Mariusz Madej, Mateusz Jabłoński, Jan Potempa, Justyna Kalinowska-Tłuścik, Grzegorz Dubin, Alexander Dömling, Tad A Holak
The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a non-genotoxic anticancer therapy. Here we present the syntheses, activities and crystal structures on two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now...
October 6, 2016: ACS Chemical Biology
Hana Cahová, Alessandro Panattoni, Pavel Kielkowski, Jindřich Fanfrlík, Michal Hocek
A complete series of 5-substituted uracil or cytosine, as well as 7-substituted 7-deazaadenine and 7-deazaguanine 2'-deoxyribonucleoside triphosphates (dNTPs) bearing substituents of increasing bulkiness (H, Me, vinyl, ethynyl, and phenyl) were systematically studied in competitive primer extension in the presence of their natural counterparts (nonmodified dNTPs), and their kinetic data were determined. The results show that modified dNTPs bearing π-electron-containing substituents (vinyl, ethynyl, Ph) are typically excellent substrates for DNA polymerases comparable to or better than natural dNTPs...
October 6, 2016: ACS Chemical Biology
Imogen A Riddell, Keli Agama, Ga Young Park, Yves Pommier, Stephen J Lippard
Drugs capable of trapping topoisomerase II (Top2), an essential enzyme that cleaves DNA to remove naturally occurring knots and tangles, can serve as potent anticancer agents. The monofunctional platinum agent phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl](NO3), is shown here to trap Top2 in addition to its known modes of inhibition of DNA and RNA polymerases. Its potency therefore combines diverse modes of action by which phenanthriplatin kills cancer cells. The observation that phenanthriplatin can act as a Top2 poison highlights opportunities to design nonclassical platinum anticancer agents with this novel mechanism of action...
October 6, 2016: ACS Chemical Biology
Yan Liu, Ying Wang, Yong Zhang, Tao Liu, Haiqun Jia, Huafei Zou, Qiangwei Fu, Yuhan Zhang, Lucy Lu, Elizabeth Chao, Holly Parker, Van Nguyen-Tran, Weijun Shen, Danling Wang, Peter G Schultz, Feng Wang
Recent studies have suggested that modulation of two or more signaling pathways can achieve substantial weight loss and glycemic stability. We have developed an approach to the generation of bifunctional antibody agonists that activate leptin receptor and GLP-1 receptor. Leptin was fused into the complementarity determining region 3 loop of the light chain alone, or in combination with exendin-4 (EX4) fused at the N-terminus of the heavy chain of Herceptin. The antibody fusions exhibit similar or increased in vitro activities on their cognate receptors, but 50-100-fold longer circulating half-lives in rodents compared to the corresponding native peptides/proteins...
October 5, 2016: ACS Chemical Biology
Joanna B Pawlak, Brett J Hos, Michel J van de Graaff, Otty A Megantari, Nico Meeuwenoord, Herman S Overkleeft, Dmitri V Filippov, Ferry Ossendorp, Sander I van Kasteren
Antigen recognition followed by the activation of cytotoxic T-cells (CTLs) is a key step in adaptive immunity, resulting in clearance of viruses and cancers. The repertoire of peptides that have the ability to bind to the major histocompatibility type-I (MHC-I) is enormous, but the available approaches to study the diversity of the peptide repertoire on a cell are limited. Here we explore the use of bioorthogonal chemistry to quantify specific peptide-MHC-I complexes (pMHC-I) on cells. We show that modifying epitope peptides with bioorthogonal groups in surface accessible positions allows wild-type-like MHC-I binding and bioorthogonal ligation using fluorogenic chromophores in combination with a Cu(I)-catalyzed Huisgen cycloaddition reaction...
October 5, 2016: ACS Chemical Biology
Yuntao Shi, Marcus J C Long, Masha M Rosenberg, Shican Li, Aimee Kobjack, Philip Lessans, Rory T Coffey, Lizbeth Hedstrom
Targeted protein degradation is a promising strategy for drug design and functional assessment. Several small molecule approaches have been developed that localize target proteins to ubiquitin ligases, inducing ubiquitination and subsequent degradation by the 26S proteasome. We discovered that the degradation of a target protein can also be induced by a recognition ligand linked to tert-butyl carbamate (Boc3)-protected arginine (B3A). Here we show that this process requires the proteasome, but does not involve ubiquitination of the target protein...
October 5, 2016: ACS Chemical Biology
Andrew K Urick, Luis Pablo Calle, Juan F Espinosa, Haitao Hu, William C K Pomerantz
To evaluate its potential as a ligand discovery tool, we compare a newly developed 1D protein-observed fluorine NMR (PrOF NMR) screening method with the well-characterized ligand-observed (1)H CPMG NMR screen. We selected the first bromodomain of Brd4 as a model system to benchmark PrOF NMR because of the high ligandability of Brd4 and the need for small molecule inhibitors of related epigenetic regulatory proteins. We compare the two methods' hit sensitivity, triaging ability, experiment speed, material consumption, and the potential for false positives and negatives...
October 5, 2016: ACS Chemical Biology
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"