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ACS Chemical Biology

Romain Rouet, Daniel Christ
We recently reported a new delivery system harnessing surface receptors for targeted uptake of CRISPR-Cas9 ribonucleoprotein (RNP) into mammalian cells (Rouet et al., JACS 2018). For this purpose, Cas9 protein was labeled with the small molecule ligand ASGRL, specific for the asialoglycoprotein receptor, enabling endosomal uptake of the RNP into human cells expressing the receptor. However, detailed mechanistic insights had remained unknown and editing efficiency low. Here we investigate the mechanism of endosomal escape as mediated by the ppTG21 peptide and outline the development of novel Cas9 or Cas12a RNP complexes with increased editing efficiency...
February 19, 2019: ACS Chemical Biology
Hua Du, Pengcheng Wang, Lin Li, Nicholas Amato, Yinsheng Wang
Genomic integrity is constantly challenged by exposure to environmental and endogenous genotoxic agents. Reactive oxygen species (ROS) represent one of the most common type of DNA damaging agents. While ROS mainly induce single-nucleobase lesions, epimeric 2-deoxyribose lesions can also be induced upon hydrogen atom abstraction from the C1', C3', or C4' carbon and the subsequent incorrect chemical repair of the carbon-centered radicals. Herein, we investigated the replicative bypass of the C1'- and C3'-epimeric lesions of the four 2'-deoxynucleosides in HEK293T human embryonic kidney cells...
February 15, 2019: ACS Chemical Biology
Jaehyoun Lee, Tae-Hee Lee
The nucleosome, the fundamental gene-packing unit comprising an octameric histone protein core wrapped around by DNA, has a flexible structure that enables dynamic gene regulation mechanisms. Histone lysine acetylation at H3K56 removes a positive charge from the histone core where it interacts with the termini of the nucleosomal DNA and acts as a critical gene regulatory signal that is implicated in transcription initiation and elongation. The predominant proposal on the biophysical role of H3K56 acetylation (H3K56ac) is that weakened electrostatic interaction between DNA termini and the histone core results in facilitated opening and subsequent disassembly of the nucleosome...
February 15, 2019: ACS Chemical Biology
Randall McNally, Qing Li, Kunhua Li, Carien Dekker, Eric Vangrevelinghe, Matthew Jones, Patrick Chene, Rainer Machauer, Thomas Radimerski, Michael J Eck
The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Exploration of analogs of screening hit BI-D1870 led to the identification of compound 2, a 123 nM ligand for the pseudokinase domain...
February 14, 2019: ACS Chemical Biology
Jon E Paczkowski, Amelia R McCready, Jian-Ping Cong, Zhijie Li, Philip D Jeffrey, Chari D Smith, Brad R Henke, Frederick M Hughson, Bonnie L Bassler
Bacteria use a cell-cell communication process called quorum sensing to coordinate collective behaviors. Quorum sensing relies on production and group-wide detection of extracellular signal molecules called autoinducers. Here, we probe the activity of the Pseudomonas aeruginosa LasR quorum-sensing receptor using synthetic agonists based on the structure of the native homoserine lactone autoinducer. The synthetic compounds range from low to high potency, and agonist activity tracks with the ability of the agonist to stabilize the LasR protein...
February 14, 2019: ACS Chemical Biology
Hiba Ahmad Zahreddine, Biljana Culjkovic-Kraljacic, Jadwiga Gasiorek, Jean Duchaine, Katherine L B Borden
Cancer therapies are plagued by resistance. Previously, we discovered a novel form of cancer drug resistance where the Glioma-associated protein 1 (GLI1) elevates UGT1A glucuronidation enzymes thereby glucuronidating cytarabine and ribavirin leading to resistance in leukemia patients. Here, we demonstrate that GLI1 imparts resistance to ~40 compounds, including FDA-approved drugs with disparate chemotypes (e.g. methotrexate and venetoclax). GLI1 indirectly elevates UGT1As via the chaperone calreticulin which is required for resistance...
February 14, 2019: ACS Chemical Biology
Tal Luzzatto-Knaan, Alexey V Melnik, Pieter C Dorrestein
Microbes use metabolic exchange to sense and respond to their changing environment. Surfactins, produced by Bacillus subtilis are extensively studied for its attributed role in biofilm formation, biosurfactant properties and antimicrobial activity, affecting the surrounding microbial consortia. Using mass spectrometry, we reveal that Paenibacillus dendritiformis, originally isolated with B. subtilis, is not antagonized by the presence of surfactins, and is actually attracted to it. We demonstrate here for the first time, that P...
February 14, 2019: ACS Chemical Biology
Yuki Nishikawa, Takayuki Miki, Masashi Awa, Keiko Kuwata, Tomonori Tamura, Itaru Hamachi
Nitric oxide (NO) is a pleiotropic signaling molecule involved in the regulation of diverse physiological and pathophysiological mechanisms in cardiovascular, nervous, and immunological systems. To understand the biological functions of NO in detail, comprehensive characterization of proteins found in high-NO concentration environments is crucial. Herein, we describe the design of NO-responsive protein labeling reagents based on N-alkoxyacyl- o-phenylenediamine as an optimal reactive scaffold. The designed molecules can label proteins in murine macrophage cells in response to endogenously produced NO...
February 14, 2019: ACS Chemical Biology
Zhuo Shang, Jaclyn M Winter, Christopher A Kauffman, Inho Yang, William Fenical
Analysis of the full genome of an environmentally-unique, halotolerant Streptomyces sp. strain GSL-6C, isolated from the Great Salt Lake, revealed a gene cluster encoding the biosynthesis of the salinipeptins, D-amino acid containing members of the rare linaridin subfamily of ribosomally synthesized and post-translationally modified peptides (RiPPs). The sequence organization of the unmodified amino acid residues in salinipeptins A-D (1-4) were suggested by genome annotation, and subsequently their sequence and post-translational modifications were defined using a range of spectroscopic techniques and chemical derivatization approaches...
February 12, 2019: ACS Chemical Biology
Tadeja Lukežič, Antoine Abou Fayad, Chantal Bader, Kirsten Harmrolfs, Johannes Bartuli, Sebastian Groß, Urška Lešnik, Fabienne Hennessen, Jennifer Herrmann, Špela Pikl, Hrvoje Petković, Rolf Müller
To combat the increasing spread of antimicrobial resistance and the shortage of novel anti-infectives, one strategy for the development of new antibiotics is to optimize known chemical scaffolds. Here, we focus on the biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline chelocardin and its potent broad-spectrum derivative 2-carboxamido-2-deacetyl-chelocardin. Heterologous biosynthetic genes were introduced into this chelocardin producer to modify functional groups and generate new derivatives...
February 12, 2019: ACS Chemical Biology
Jessica L Alexander, Zechariah Thompson, Zhen Yu, J A Cowan
Antimicrobial peptides (AMP's) are short, amphipathic peptides that are typically cationic in sequence and display broad-spectrum activity against bacteria, fungi, and protists. Herein, we report the effect of appending the amino terminal copper and nickel binding motif (ATCUN) to Sub5. The Cu-ATCUN derivatives show a two to three-fold increase in antimicrobial activity for a variety of microbes, relative to Sub5, with MICs as low as 0.3 ± 0.1 µM towards Enterococcus faecium. Sub5 and the ATCUN derivatives bind both plasmid DNA and 16s A-site rRNA with low micromolar affinity...
February 11, 2019: ACS Chemical Biology
Martin Delguste, Nadia Peerboom, Grégoire Le Brun, Edward Trybala, Sigvard Olofsson, Tomas Bergström, David Alsteens, Marta Bally
Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells...
February 8, 2019: ACS Chemical Biology
Denis T Akan, Jennifer E Howes, Jiqing Sai, Allison L Arnold, Yugandhar Beesetty, Jason Phan, Edward T Olejniczak, Alex G Waterson, Stephen W Fesik
Activating mutations in RAS lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting RAS may perturb multiple signaling pathways simultaneously. One method for modulating RAS signaling is to target the activity of the guanine nucleotide exchange factor SOS1. Our laboratory has discovered compounds that bind to SOS1 and activate RAS. Interestingly, these SOS1 agonist compounds elicit biphasic modulation of ERK phosphorylation and simultaneous inhibition of AKT phosphorylation levels...
February 8, 2019: ACS Chemical Biology
Yen-Chih Wang, Nathan P Westcott, Matthew E Griffin, Howard C Hang
The peptidoglycan fragments -D-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl-dipeptide (MDP) are microbial-specific metabolites that activate intracellular pattern recognition receptors and stimulate immune signaling pathways. While extensive structure-activity studies have demonstrated that these bacterial cell wall metabolites trigger NOD1- and NOD2-dependent signaling, their direct binding to these innate immune receptors or other proteins in mammalian cells has not been established. To characterize these fundamental microbial metabolite-host interactions, we synthesized a series of peptidoglycan metabolite photoaffinity reporters and evaluated their crosslinking to NOD1 and NOD2 in mammalian cells...
February 8, 2019: ACS Chemical Biology
Steven C Boggess, Shivaani S Gandhi, Brian A Siemons, Nathaniel Huebsch, Kevin E Healy, Evan W Miller
The ability to non-invasively monitor membrane potential dynamics in excitable cells like neurons and cardiomyocytes promises to revolutionize our understanding of the physiology and pathology of the brain and heart. Here, we report the design, synthesis, and application of a new class of fluorescent voltage indicators that make use of a fluorene-based molecular wire as a voltage-sensing domain to provide fast and sensitive measurements of membrane potential in both mammalian neurons and human-derived cardiomyocytes...
February 8, 2019: ACS Chemical Biology
Michael Roy, Sandra Winkler, Scott J Hughes, Claire Whitworth, Michael Galant, William Farnaby, Klaus Rumpel, Alessio Ciulli
Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target:PROTAC:ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation...
February 5, 2019: ACS Chemical Biology
Josie A Silvaroli, Made Airanthi K Widjaja-Adhi, Thomas Trischman, Sylwia Chelstowska, Samantha Horwitz, Surajit Banerjee, Philip D Kiser, William S Blaner, Marcin Golczak
Cellular retinol-binding proteins (CRBPs) facilitate the uptake and intracellular transport of vitamin A. They integrate retinoid metabolism, playing an important role in regulating the synthesis of bioactive vitamin A metabolites. Thus, CRBPs constitute potential pharmacological targets to modulate cellular retinoid status that in turn may have applications in the treatment of certain immunological, metabolic, and ocular disorders. Here we identify abnormal cannabidiol (abn-CBD) as a non-retinoid inhibitor of cellular retinol-binding protein 1 (CRBP1)...
February 5, 2019: ACS Chemical Biology
Francesca Troilo, Daniela Bonetti, Christophe Bignon, Sonia Longhi, Stefano Gianni
The interaction between NTAIL and XD from measles virus represents a paradigmatic example of molecular recognition between an intrinsically disordered protein and a folded partner. By binding to XD, a small portion of NTAIL (classically denoted as MoRE) undergoes a disorder to order transition, populating an α-helical structure, while the reminder of the protein remains disordered. Here we demonstrate an unexpected crosstalk between such a disordered region and the adjacent MoRE. This result was obtained by producing a series of truncation and site-directed variants of NTAIL while measuring the effects on the kinetics of folding and binding...
February 4, 2019: ACS Chemical Biology
Liang Ma, Chen Yang, Lianqi Huang, Yuchen Chen, Yang Li, Cheng Cheng, Biao Cheng, Ling Zheng, Kun Huang
The aggregation of human islet amyloid polypeptide (hIAPP) is one of the triggering factors of type 2 diabetes mellitus (T2DM). hIAPP is co-synthesized, co-stored and co-secreted with insulin in pancreatic β-cells, and insulin inhibits hIAPP aggregation. In T2DM patients, long-term hyperglycemia causes glycation of near 10% of total insulin. The glycation not only modifies insulin but also crosslinks insulin into oligomers. However, the effect of glycated human insulin on hIAPP aggregation is unknown. In this study, four physiologically relevant monosaccharides, methylglyoxal, glucose, fructose and ribose were used to glycate human insulin and two C-terminus truncated insulin analogues...
February 4, 2019: ACS Chemical Biology
Yaya Li, Weibing Liu, Qi Tang, Xinqi Fan, Yi Hao, Ling Gao, Zefan Li, Bo Cheng, Xing Chen
Intercellular communication via gap junctions is crucial for orchestrating behaviors of multicellular systems. Imaging methods and electrophysiological techniques have been widely used to identify gap junctions and map the gap-junction-connected cell networks. However, analyzing gene expression within a gap-junction network remains challenging. Herein, we report the development of bio-orthogonal recording of translation in adjacent cells connected by gap junctions (BORTAC-GJ), a gap-junction-dependent protein tagging method based on local activation of clickable amino acid analogues that pass through gap junctions and are metabolically incorporated into nascent proteins...
February 4, 2019: ACS Chemical Biology
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