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Cell Chemical Biology

Bainan Wu, Surya K De, Anna Kulinich, Ahmed F Salem, Jordan Koeppen, Rengang Wang, Elisa Barile, Si Wang, Dongxiang Zhang, Iryna Ethell, Maurizio Pellecchia
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is critical for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The molecules exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the molecules appear to act as agonists for the receptor in certain surrogate cellular assays...
February 8, 2017: Cell Chemical Biology
Rhushikesh A Kulkarni, Andrew J Worth, Thomas T Zengeya, Jonathan H Shrimp, Julie M Garlick, Allison M Roberts, David C Montgomery, Carole Sourbier, Benjamin K Gibbs, Clementina Mesaros, Yien Che Tsai, Sudipto Das, King C Chan, Ming Zhou, Thorkell Andresson, Allan M Weissman, W Marston Linehan, Ian A Blair, Nathaniel W Snyder, Jordan L Meier
Non-enzymatic protein modification driven by thioester reactivity is thought to play a major role in the establishment of cellular lysine acylation. However, the specific protein targets of this process are largely unknown. Here we report an experimental strategy to investigate non-enzymatic acylation in cells. Specifically, we develop a chemoproteomic method that separates thioester reactivity from enzymatic utilization, allowing selective enrichment of non-enzymatic acylation targets. Applying this method to cancer cell lines identifies numerous candidate targets of non-enzymatic acylation, including several enzymes in lower glycolysis...
January 31, 2017: Cell Chemical Biology
Frank Fontaine, Jeroen Overman, Mehdi Moustaqil, Sreeman Mamidyala, Angela Salim, Kamesh Narasimhan, Nina Prokoph, Avril A B Robertson, Linda Lua, Kirill Alexandrov, Peter Koopman, Robert J Capon, Emma Sierecki, Yann Gambin, Ralf Jauch, Matthew A Cooper, Johannes Zuegg, Mathias Francois
Pharmacological modulation of transcription factors (TFs) has only met little success over the past four decades. This is mostly due to standard drug discovery approaches centered on blocking protein/DNA binding or interfering with post-translational modifications. Recent advances in the field of TF biology have revealed a central role of protein-protein interaction in their mode of action. In an attempt to modulate the activity of SOX18 TF, a known regulator of vascular growth in development and disease, we screened a marine extract library for potential small-molecule inhibitors...
January 27, 2017: Cell Chemical Biology
Daiqing Liao
Bromodomains are protein domains that serve as "readers" of acetylated lysine marks and mediate DNA-templated processes. In this issue of Cell Chemical Biology, Olzscha et al. (2017) report that the CBP/p300 bromodomains mediate the formation of amyloid-like aggregates and that inhibitors specific to these bromodomains reduce the degree of protein aggregation and mitigate HDAC inhibitor-induced cytotoxicity.
January 26, 2017: Cell Chemical Biology
Emily S Weyburne, Owen M Wilkins, Zhe Sha, David A Williams, Alexandre A Pletnev, Gerjan de Bruin, Hermann S Overkleeft, Alfred L Goldberg, Michael D Cole, Alexei F Kisselev
The proteasome inhibitors carfilzomib (Cfz) and bortezomib (Btz) are used successfully to treat multiple myeloma, but have not shown clinical efficacy in solid tumors. Here we show that clinically achievable inhibition of the β5 site of the proteasome by Cfz and Btz does not result in loss of viability of triple-negative breast cancer cell lines. We use site-specific inhibitors and CRISPR-mediated genetic inactivation of β1 and β2 to demonstrate that inhibiting a second site of the proteasome, particularly the β2 site, sensitizes cell lines to Btz and Cfz in vitro and in vivo...
January 25, 2017: Cell Chemical Biology
Lisa Asano, Mizuki Watanabe, Yuta Ryoden, Kousuke Usuda, Takuya Yamaguchi, Bilon Khambu, Megumi Takashima, Shin-Ichi Sato, Juro Sakai, Kazuo Nagasawa, Motonari Uesugi
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. SREBP activation is regulated by a negative feedback loop in which sterols bind to SREBP cleavage-activating protein (SCAP), an escort protein essential for SREBP activation, or to insulin-induced genes (Insigs) (endoplasmic reticulum [ER] anchor proteins), sequestering the SREBP-SCAP-Insig complex in the ER. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation...
January 23, 2017: Cell Chemical Biology
Breanna Ford, Leslie A Bateman, Leilani Gutierrez-Palominos, Robin Park, Daniel K Nomura
Glyphosate, the active ingredient in the herbicide Roundup, is one of the most widely used pesticides in agriculture and home garden use. Whether glyphosate causes any mammalian toxicity remains highly controversial. While many studies have associated glyphosate with numerous adverse health effects, the mechanisms underlying glyphosate toxicity in mammals remain poorly understood. Here, we used activity-based protein profiling to map glyphosate targets in mice. We show that glyphosate at high doses can be metabolized in vivo to reactive metabolites such as glyoxylate and react with cysteines across many proteins in mouse liver...
January 19, 2017: Cell Chemical Biology
Jing Liu, Jiaxin Hu, Andrew T Ludlow, Jacqueline T Pham, Jerry W Shay, Jeffrey D Rothstein, David R Corey
The chromosome 9 open reading frame 72 (c9orf72) gene contains a hexanucleotide (GGGGCC) repeat expansion responsible for many cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mutant intronic RNA forms "foci" within nuclei, but the connection between transcript expression, foci, and biochemical disease mechanisms is unclear. Knowing the absolute numbers of cellular RNAs, in any system, is important for understanding the molecular mechanisms of natural physiology, disease, and drug action...
January 18, 2017: Cell Chemical Biology
Kong-Hung Sze, Wai-Hei Lam, Hongmin Zhang, Yi-Hong Ke, Man-Kit Tse, Patrick C Y Woo, Susanna K P Lau, Candy C Y Lau, Jian-Piao Cai, Edward T K Tung, Raymond K C Lo, Simin Xu, Richard Y T Kao, Quan Hao, Kwok-Yung Yuen
Talaromyces (Penicillium) marneffei is one of the leading causes of systemic mycosis in immunosuppressed or AIDS patients in Southeast Asia. How this intracellular pathogen evades the host immune defense remains unclear. We provide evidence that T. marneffei depletes levels of a key proinflammatory lipid mediator arachidonic acid (AA) to evade the host innate immune defense. Mechanistically, an abundant secretory mannoprotein Mp1p, shown previously to be a virulence factor, does so by binding AA with high affinity via a long hydrophobic central cavity found in the LBD2 domain...
January 16, 2017: Cell Chemical Biology
Sylvain Meylan, Caroline B M Porter, Jason H Yang, Peter Belenky, Arnaud Gutierrez, Michael A Lobritz, Jihye Park, Sun H Kim, Samuel M Moskowitz, James J Collins
Metabolically dormant bacteria present a critical challenge to effective antimicrobial therapy because these bacteria are genetically susceptible to antibiotic treatment but phenotypically tolerant. Such tolerance has been attributed to impaired drug uptake, which can be reversed by metabolic stimulation. Here, we evaluate the effects of central carbon metabolite stimulations on aminoglycoside sensitivity in the pathogen Pseudomonas aeruginosa. We identify fumarate as a tobramycin potentiator that activates cellular respiration and generates a proton motive force by stimulating the tricarboxylic acid (TCA) cycle...
January 16, 2017: Cell Chemical Biology
Pan Wu, Dan Wan, Gudan Xu, Gui Wang, Hongmin Ma, Tingting Wang, Yaojie Gao, Jianzhao Qi, Xiaoxia Chen, Jian Zhu, Yong-Quan Li, Zixin Deng, Wenqing Chen
Pentostatin (PTN, deoxycoformycin) and arabinofuranosyladenine (Ara-A, vidarabine) are purine nucleoside antibiotics used clinically to treat hematological cancers and human DNA virus infections, respectively. PTN has a 1,3-diazepine ring, and Ara-A is an adenosine analog with an intriguing epimerization at the C-2' hydroxyl group. However, the logic underlying the biosynthesis of these interesting molecules has long remained elusive. Here, we report that the biosynthesis of PTN and Ara-A employs an unusual protector-protégé strategy...
January 12, 2017: Cell Chemical Biology
Ken Ishikawa, Scott H Medina, Joel P Schneider, Amar J S Klar
Although resistance toward small-molecule chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains unexplored. Anticancer peptides (ACPs) are a class of such agents that disrupt tumor cell membranes through rapid and non-stereospecific mechanisms, encouraging the perception that cellular resistance toward ACPs is unlikely to occur. We demonstrate that eukaryotic cells can, indeed, develop resistance to the model oncolytic peptide SVS-1, which preferentially disrupts the membranes of cancer cells...
January 9, 2017: Cell Chemical Biology
Katharina Rox, Manfred Rohde, Gursharan Singh Chhatwal, Rolf Müller
Bacterial pathogens use invasion into human cells as a strategy to escape not only the host's immune response, but also anti-bacterial treatment. This often leads to persistence and enables reinitiation of the infection process at a later time point. Here, we show that a family of myxobacterial metabolites, disorazoles, block invasion of group A Streptococcus (GAS) into human epithelial cells. Mechanistically, disorazoles target ezrin, a host protein involved in linking microfilaments to the membrane, and affect invasion most likely by interfering with dynamic phosphorylation of ezrin...
January 5, 2017: Cell Chemical Biology
David M J Lilley
Riboswitches are widespread in the bacterial kingdom, where they regulate gene expression in response to different small molecules and ions. However, some remain orphans with no known endogenous ligand. Three recently published papers (Battaglia et al., 2017; Nelson et al., 2017; and Reiss et al., 2017) de-orphanize a widespread ykkC element, showing that it responds to guanidine and elaborating on how that response is mediated.
February 16, 2017: Cell Chemical Biology
Gregory R Wagner, Matthew D Hirschey
Non-enzymatic modification of proteins by acyl-CoA species involved in intermediary metabolism is a possible explanation for widespread protein acylation. In this issue, Kulkarni et al. (2017) develop a set of chemoproteomic probes to interrogate the role of malonyl-CoA in mediating protein malonylation and find malonylation influences glycolysis in cancer cells.
February 16, 2017: Cell Chemical Biology
Mark Rolfe
Proteasome inhibitors have revolutionized the treatment of multiple myeloma but have had disappointing results when treating solid tumors. The work of Weyburne et al. (2017), published in this issue of Cell Chemical Biology, sheds some light on this conundrum and suggests a novel approach to achieve solid tumor efficacy.
February 16, 2017: Cell Chemical Biology
Dorival Martins, Dao Nguyen
In this issue of Cell Chemical Biology, Meylan et al. (2017) examine how stimulation of central carbon metabolism of Pseudomonas aeruginosa modulates aminoglycoside lethality in tolerant bacteria. They identify fumarate as a tobramycin potentiator that stimulates proton motive force-dependent drug uptake and increases respiration-dependent killing.
February 16, 2017: Cell Chemical Biology
Joshua G Pierce
In this issue of Cell Chemical Biology, Ishikawa et al. (2017) demonstrate that the loss of cell-surface anionic saccharides can impart resistance toward anticancer peptides. This study provides the first insight into potential resistance mechanisms toward cationic lytic peptides and highlights the important, yet previously unappreciated, role cell-surface glycans can play in cellular resistance mechanisms.
February 16, 2017: Cell Chemical Biology
Yongqi Shao, Bosheng Chen, Chao Sun, Keishi Ishida, Christian Hertweck, Wilhelm Boland
Insects develop efficient antimicrobial strategies to flourish in a bacterial world. It has long been proposed that native gut microbiota is an important component of host defense; however, the responsible species have rarely been isolated to elucidate the mechanism of action. Here we show that the dominant symbiotic bacterium Enterococcus mundtii associated with the generalist herbivore Spodoptera littoralis actively secretes a stable class IIa bacteriocin (mundticin KS) against invading bacteria, but not against other gut residents, facilitating the normal development of host gut microbiota...
January 19, 2017: Cell Chemical Biology
Daniel Braga, Gerald Lackner
In this issue of Cell Chemical Biology, Li et al. (2017) report on the biosynthesis of the monobactam sulfazecin by Pseudomonas acidophila and hypothesize a novel mechanism of β-lactam ring formation. As monobactam antibiotics are unaffected by some emerging resistance mechanisms (particularly metallo-β-lactamases), this discovery opens prospects to engineer β-lactam antibiotics against multi-drug resistant pathogens.
January 19, 2017: Cell Chemical Biology
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