Abstract:
:Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 μM against PR8 H1N1 influenza A in MDCK cells.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Bauman JD,Patel D,Baker SF,Vijayan RS,Xiang A,Parhi AK,Martínez-Sobrido L,LaVoie EJ,Das K,Arnold Edoi
10.1021/cb400400jsubject
Has Abstractpub_date
2013-11-15 00:00:00pages
2501-8issue
11eissn
1554-8929issn
1554-8937journal_volume
8pub_type
杂志文章abstract::Terpenes are ubiquitous natural chemicals with diverse biological functions spanning all three domains of life. In specialized metabolism, the active sites of terpene synthases (TPSs) evolve in shape and reactivity to direct the biosynthesis of a myriad of chemotypes for organismal fitness. As most terpene biosynthesi...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00539
更新日期:2015-11-20 00:00:00
abstract::Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are t...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300709g
更新日期:2013-07-19 00:00:00
abstract::Dysregulated activity of the protease matriptase is a key contributor to aggressive tumor growth, cancer metastasis, and osteoarthritis. Methods for the detection and quantification of matriptase activity and inhibition would be useful tools. To address this need, we developed a matriptase-sensitive protein biosensor ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00715
更新日期:2018-01-19 00:00:00
abstract::Originally discovered as part of an adaptive bacterial defense system against the invasion of foreign phages, programmable CRISPR-Cas nucleases have emerged as remarkable enzymes with transformative potential for both biological research and clinical application. CRISPR-Cas nucleases likely evolved in their natural co...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00847
更新日期:2018-02-16 00:00:00
abstract::The indole side chain of tryptophan has latent nucleophilic reactivity at both N1 and all six (nonbridgehead) carbons, which is not generally manifested in post-translational reactions of proteins. On the other hand, all seven positions can be prenylated by the primary metabolite Δ(2)-isopentenyl diphosphate by dimeth...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb500695k
更新日期:2014-12-19 00:00:00
abstract::Understanding the complex biochemical mechanisms that underlie the regulation, toxicity, and protein binding of metal ions requires the ability to analyze the metal content of individual proteins in complex mixtures. In this issue of ACS Chemical Biology, a technique combining gel electrophoresis with synchrotron X-ra...
journal_title:ACS chemical biology
pub_type: 评论,杂志文章
doi:10.1021/cb100145z
更新日期:2010-06-18 00:00:00
abstract::Kinases constitute an important class of therapeutic targets being explored both by academia and the pharmaceutical industry. The major focus of this effort was directed toward the identification of ATP competitive inhibitors. Although it has long been recognized that the intracellular concentration of ATP is very dif...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb5002125
更新日期:2014-07-18 00:00:00
abstract::Aldehydes are key intermediates in many cellular processes, from endogenous metabolic pathways like glycolysis to undesired exogenously induced processes such as lipid peroxidation and DNA interstrand cross-linking. Alkyl aldehydes are well documented to be cytotoxic, affecting the functions of DNA and protein, and th...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b00269
更新日期:2016-08-19 00:00:00
abstract::Ca(II) ions are critical for the proper function of neurons by contributing to synaptic signaling and regulating neuronal plasticity. Dysregulation of Ca(II) is associated with a number of pathologies that cause neurodegeneration; therefore the ability to monitor Ca(II) intracellularly is an important target for molec...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00638
更新日期:2020-02-21 00:00:00
abstract::Several C-β-d-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in h...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00172
更新日期:2019-07-19 00:00:00
abstract::Cysteine residues on proteins play key roles in catalysis and regulation. These functional cysteines serve as active sites for nucleophilic and redox catalysis, sites of allosteric regulation, and metal-binding ligands on proteins from diverse classes including proteases, kinases, metabolic enzymes, and transcription ...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb3005269
更新日期:2013-02-15 00:00:00
abstract::Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00056
更新日期:2017-05-19 00:00:00
abstract::It is well established that aberrant cellular biochemical activity is strongly linked to the formation and progression of various cancers. Assays that could aid in cancer diagnostics, assessing anticancer drug resistance, and in the discovery of new anticancer drugs are highly warranted. In recent years, a large numbe...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/acschembio.8b00014
更新日期:2018-07-20 00:00:00
abstract::Histone post-translational modifications (PTMs) are crucial for many cellular processes including mitosis, transcription, and DNA repair. The cellular readout of histone PTMs is dependent on both the chemical modification and histone site, and the array of histone PTMs on chromatin is dynamic throughout the eukaryotic...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00651
更新日期:2020-01-17 00:00:00
abstract::The gibberellin (GA) phytohormones are produced not only by plants but also by fungi and bacteria. Previous characterization of a cytochrome P450 (CYP)-rich GA biosynthetic operon found in many symbiotic, nitrogen-fixing rhizobia led to the elucidation of bacterial GA biosynthesis and implicated GA9 as the final produ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b01038
更新日期:2017-04-21 00:00:00
abstract::Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge, and new strategies are required. Herein, we describe the development of the first highly selective and cell-permeable inhibitor of c-Src, a key signaling kinase in cancer. Our strategy involves extensio...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300172e
更新日期:2012-08-17 00:00:00
abstract::miRNAs are small non-coding RNAs that regulate about 60% of mammalian genes by modulating their transcript levels. Network scale studies of miRNA-mediated regulatory circuits demonstrate the central importance of this class of small RNA in the maintenance of biological robustness. More recently, several reports have d...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300650y
更新日期:2013-05-17 00:00:00
abstract::Recent studies have shown that cholesterol plays a significant role in the ability of Toxin A from Clostridium difficile to enter eukaryotic cells. The translocation process is one of three major steps during intoxication that could be targeted for intervention against the severe antibiotic-associated diarrhea caused ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb600133b
更新日期:2006-04-25 00:00:00
abstract::Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The current treatment options for AD are limited to ameliorating cognitive decline temporarily and not reversing or preventing the progression of dementia. Hence, more effective therapeutic strategies are needed ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00851
更新日期:2020-12-18 00:00:00
abstract::We have developed an improved tool for imaging acidic tumors by reporting the insertion of a transmembrane helix: the pHLIP-Fluorescence Insertion REporter (pHLIP-FIRE). In acidic tissues, such as tumors, peptides in the pHLIP family insert as α-helices across cell membranes. The cell-inserting end of the pHLIP-FIRE p...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb500388m
更新日期:2014-11-21 00:00:00
abstract::Hydrogen sulfide (H2S) is an endogenously produced gas that is toxic at high concentrations. It is eliminated by a dedicated mitochondrial sulfide oxidation pathway, which connects to the electron transfer chain at the level of complex III. Direct reduction of cytochrome c (Cyt C) by H2S has been reported previously b...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00463
更新日期:2018-08-17 00:00:00
abstract::RNA modifications play important roles in RNA structures and regulation of gene expression and translation. We report the first RNA modification on the phosphate, the RNA phosphorothioate (PS) modification, discovered in both prokaryotes and eukaryotes. The PS modification is also first reported on nucleic acids of eu...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00163
更新日期:2020-06-19 00:00:00
abstract::Polyhalogenated dibenzo-p-dioxins are arguably among the most toxic molecules known to man. In addition to anthropogenic sources, marine invertebrates also harbor polybrominated dibenzo-p-dioxins of as yet unknown biogenic origin. Here, we report that the bmp gene locus in marine bacteria, a recently characterized sou...
journal_title:ACS chemical biology
pub_type: 信件
doi:10.1021/cb5004338
更新日期:2014-09-19 00:00:00
abstract::Zinc plays both physiological and pathological roles in biology, making it of increasing interest. To date, intracellular free zinc has been measured in cell types supplemented with or enriched in zinc, such as hippocampal neurons. Here we quantitatively image intracellular exchangeable zinc in an ordinary resting cel...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb500043a
更新日期:2006-03-17 00:00:00
abstract::Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post-translational oxidation of cysteine or serine side chains, this aldehyde-functionalized residue participates in a unique and highly efficient catalytic mechanism for sulfate ester...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb500897w
更新日期:2015-01-16 00:00:00
abstract::Whereas the C. elegans genome was sequenced many years ago, the role of small molecule signals in its biology is still poorly understood. A recent publication reports the identification of two steroidal signaling molecules that regulate C. elegans reproductive development and dauer diapause via the nuclear receptor DA...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb600173t
更新日期:2006-05-23 00:00:00
abstract::Light-activated protein domains provide a convenient, modular, and genetically encodable sensor for optogenetics and optobiology. Although these domains have now been deployed in numerous systems, the precise mechanism of photoactivation and the accompanying structural dynamics that modulate output domain activity rem...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00543
更新日期:2020-10-16 00:00:00
abstract::Virus entry depends on biomolecular recognition at the surface of cell membranes. In the case of glycolipid receptors, these events are expected to be influenced by how the glycan epitope close to the membrane is presented to the virus. This presentation of membrane-associated glycans is more restricted than that of g...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00152
更新日期:2017-05-19 00:00:00
abstract::Unrelated ligands, often found in drug discovery campaigns, can bind to the same receptor, even with the same protein residues. To investigate how this might occur, and whether it might be typically possible to find unrelated ligands for the same drug target, we sought examples of topologically unrelated ligands that ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00443
更新日期:2018-09-21 00:00:00
abstract::The cell utilizes the Keap1/Nrf2-ARE signaling pathway to detoxify harmful chemicals in order to protect itself from oxidative stress and to maintain its reducing environment. When exposed to oxidative stress and xenobiotic inducers, the redox sensitive Keap1 is covalently modified at specific cysteine residues. Conse...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb4000103
更新日期:2013-08-16 00:00:00