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Covalent inhibitors

Hongik Hwang, Hyewhon Rhim
Post-translational modifications (PTMs) covalently modify proteins and diversify protein functions. Along with protein phosphorylation, another common PTM is the addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and/or threonine residues. O-GlcNAc modification is similar to phosphorylation in that it occurs to serine and threonine residues and cycles on and off with a similar time scale. However, a striking difference is that the addition and removal of the O-GlcNAc moiety on all substrates are mediated by the two enzymes regardless of proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively...
December 6, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Gerd Mittelstädt, Wanting Jiao, Emma Livingstone, Gert-Jan Moggré, Ali Reza Nazmi, Emily J Parker
ATP-phosphoribosyltransferase (ATP-PRT) catalyses the first committed step of histidine biosynthesis in plants and micro-organisms. Two forms of ATP-PRT have been reported, which differ in their molecular architecture and mechanism of allosteric regulation. The short-form ATP-PRT is a hetero-octamer, with four HisG chains that comprise only the catalytic domains and four separate chains of HisZ required for allosteric regulation by histidine. The long-form ATP-PRT is homohexameric, with each chain comprising two catalytic domains and a covalently linked regulatory domain that binds histidine as an allosteric inhibitor...
December 5, 2017: Biochemical Journal
S Yilmaz, I Yalcin, S Okten, F K Onurdag, E Aki-Yalcin
Acinetobacter baumannii has emerged as an important pathogen for nosocomial infections having high morbidity and mortality. This pathogen is notorious for antimicrobial resistance to many common antimicrobial agents including fluoroquinolones, which have both intrinsic and acquired resistance mechanisms. Fluoroquinolones targeting the bacterial topoisomerase II (DNA gyrase and Topo IV) show potent broad-spectrum antibacterial activity by the stabilization of the covalent enzyme-DNA complex. However, their efficacy is now being threatened by an increasing prevalence of resistance...
November 2017: SAR and QSAR in Environmental Research
James V Michael, Lawrence E Goldfinger
For decades oncogenic RAS proteins were considered undruggable due to a lack of accessible binding pockets on the protein surfaces. Seminal early research in RAS biology uncovered the basic paradigm of post-translational isoprenylation of RAS polypeptides, typically with covalent attachment of a farnesyl group, leading to isoprenyl-mediated RAS anchorage at the plasma membrane and signal initiation at those sites. However, the failure of farnesyltransferase inhibitors to translate to the clinic stymied anti-RAS therapy development...
December 1, 2017: Seminars in Cancer Biology
Richard C Petersen
A breakthrough has been discovered in pathology chemistry related to increasing molecular structure that can interfere with oxygen diffusion through cell membranes. Free radicals can crosslink unsaturated low-viscosity fatty acid oils by chain-growth polymerization into more viscous liquids and even solids. Free radicals are released by mitochondria in response to intermittent hypoxia that can increase membrane molecular organization to reduce fluidity and oxygen diffusion in a possible continuing vicious cycle toward pathological disease...
2017: AIMS Biophysics
Wataru Kawahata, Tokiko Asami, Takayuki Irie, Masaaki Sawa
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.
November 24, 2017: Bioorganic & Medicinal Chemistry Letters
Sijun Pan, Se-Young Jang, Si Si Liew, Jiaqi Fu, Danyang Wang, Jun-Seok Lee, Shao Q Yao
Chemical probes are powerful tools for interrogating small molecule-target interactions. With additional fluorescence Turn-ON functionality, such probes might enable direct measurements of target engagement in live mammalian cells. Fluorogenic small molecules capable of covalently and selectively modifying endogenous targets in an activity-based manner are however rare. Herein, we report DNS-pE as the first small molecule that can selectively label endogenous 3-phosphoglycerate dehydrogenase (PHGDH) from various mammalian cells...
November 28, 2017: Angewandte Chemie
Takeshi Yamaura, Toshiyuki Nakatani, Ken Uda, Hayato Ogura, Wigyon Shin, Naoya Kurokawa, Koichi Saito, Norie Fujikawa, Tomomi Date, Masaru Takasaki, Daisuke Terada, Atsushi Hirai, Akimi Akashi, Fangli Chen, Yoshiya Adachi, Yuichi Ishikawa, Fumihiko Hayakawa, Shinji Hagiwara, Tomoki Naoe, Hitoshi Kiyoi
An activating mutation of FLT3 is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression...
November 29, 2017: Blood
Adrian C D Fuchs, Lorena Maldoner, Katharina Hipp, Marcus D Hartmann, Jörg Martin
Eukaryotic and archaeal proteasomes are paradigms for self-compartmentalizing proteases. To a large extent, their function requires the interplay with hexameric ATPases associated with diverse cellular activities (AAA+) that act as substrate unfoldases. Bacteria have various types of self-compartmentalizing proteases; in addition to the proteasome itself, these include the proteasome homolog HslV, which functions together with the AAA+ ATPase HslU; the ClpP protease with its partner AAA+ ATPase ClpX; and Anbu, a recently characterized ancestral proteasome variant...
November 28, 2017: Journal of Biological Chemistry
Nicholas J Fowler, Christopher F Blanford, Sam P de Visser, Jim Warwicker
Large-scale characterisation of cysteine modification is enabling study of the physicochemical determinants of reactivity. We find that location of cysteine at the amino terminus of an α-helix, associated with activity in thioredoxins, is under-represented in human protein structures, perhaps indicative of selection against background reactivity. An amino-terminal helix location underpins the covalent linkage for one class of kinase inhibitors. Cysteine targets for S-palmitoylation, S-glutathionylation, and S-nitrosylation show little correlation with pKa values predicted from structures, although flanking sequences of S-palmitoylated sites are enriched in positively-charged amino acids, which could facilitate palmitoyl group transfer to substrate cysteine...
November 27, 2017: Scientific Reports
Mahmood H Jasim, Daniel L Rathbone
The major function of the enzyme human tissue transglutaminase (TG2) is the crosslinking of proteins via a transamidation between the γ-carboxamide of a glutamine and the ε-amino group of a lysine. Overexpression of TG2 can lead to undesirable outcomes and has been linked to conditions such as fibrosis, celiac disease and neurodegenerative diseases. Accordingly, TG2 is a tempting drug target. The most effective TG2 inhibitors to date are small-molecule peptidomimetics featuring electrophilic warheads that irreversibly modify the active site catalytic cysteine (CYS277)...
November 22, 2017: Journal of Molecular Graphics & Modelling
Eliseu A Münchow, Marco C Bottino
Purpose of review: To present an overview on the main agents (i.e., biomolecules and nanocompounds) and/or strategies currently available to amplify or stabilize resin-dentin bonding. Recent findings: According to studies retrieved for full text reading (2014-2017), there are currently six major strategies available to overcome resin-dentin bond degradation: (i) use of collagen crosslinking agents, which may form stable covalent bonds with collagen fibrils, thus strengthening the hybrid layer; (ii) use of antioxidants, which may allow further polymerization reactions over time; (iii) use of protease inhibitors, which may inhibit or inactivate metalloproteinases; (iv) modification of the bonding procedure, which may be performed by using the ethanol wet-bonding technique or by applying an additional adhesive (hydrophobic) coating, thereby strengthening the hybrid layer; (v) laser treatment of the substrate prior to bonding, which may cause specific topographic changes in the surface of dental substrates, increasing bonding efficacy; and (vi) reinforcement of the resin matrix with inorganic fillers and/or remineralizing agents, which may positively enhance physico-mechanical properties of the hybrid layer...
September 2017: Current Oral Health Reports
Lan Li, Chengke Luo, Zhenwei Song, Eduardo Reyes-Vargas, Fred Clayton, Jufang Huang, Peter Jensen, Xinjian Chen
The finding of HER2 overexpression in osteosarcoma (OS) makes HER2 a potential therapeutic target. However, studies indicate OS cells are nonresponsive to anti-HER2 antibody trastuzumab (TRA) therapy. We established stable, non-covalent association of TRA with nanomaterial graphene oxide (GO) to generated multivalent TRA/GO complexes that demonstrated markedly enhanced HER2-binding activity and capacity to rapidly kill OS cells. TRA/GO simultaneously induced oxidative stress and HER2 signaling in the target cells, leading to rapid depletion of the cellular inhibitors of apoptosis protein (cIAP) and caspase 8, formation of RIP1/RIPK3/MLKL necroptosome and necroptosis of the OS cells...
November 20, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
Pedro Merino, Ignacio Delso, Jessika Valero-Gonzalez, Fernando Gomollon-Bel, Jorge Castro-Lopez, Wenxia Fang, Iva Navratilova, Daan M F van Aalten, Tomas Tejero, Ramon Hurtado-Guerrero
Fungal beta-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi/yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Here, we report a multidisciplinary approach, based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4...
November 22, 2017: ChemMedChem
John F Darby, Masakazu Atobe, James D Firth, Paul Bond, Gideon J Davies, Peter O'Brien, Roderick E Hubbard
Modulation of enzyme activity is a powerful means of probing cellular function and can be exploited for diverse applications. Here, we explore a method of enzyme activation where covalent tethering of a small molecule to an enzyme can increase catalytic activity (kcat/KM) up to 35-fold. Using a bacterial glycoside hydrolase, BtGH84, we demonstrate how small molecule "fragments", identified as activators in free solution, can be covalently tethered to the protein using Michael-addition chemistry. We show how tethering generates a constitutively-activated enzyme-fragment conjugate, which displays both improved catalytic efficiency and increased susceptibility to certain inhibitor classes...
November 1, 2017: Chemical Science
Guiqin He, Xiangyu Yang, Guo Wang, Junxia Qi, Rui Mao, Zhengping Wu, Zikai Zhou
In the brain, de novo gene expression driven by learning-associated neuronal activities is critical for the formation of long-term memories. However, the signaling machinery mediating neuronal activity-induced gene expression, especially the rapid transcription of immediate-early genes (IEGs) remains unclear. Cyclin-dependent kinases (Cdks) are a family of serine/threonine kinases that have been firmly established as key regulators of transcription processes underling coordinated cell cycle entry and sequential progression in nearly all types of proliferative cells...
2017: Frontiers in Molecular Neuroscience
Meng S Choy, Mark Swingle, Brandon D'Arcy, Kevin Abney, Scott F Rusin, Arminja N Kettenbach, Rebecca Page, Richard E Honkanen, Wolfgang Peti
Selective inhibitors for each serine/threonine phosphatase (PPP) are essential to investigate the biological actions of PPPs and to guide drug development. Although multiple organisms (cyanobacteria, dinoflagellates, beetles, etc.) produce natural toxins that bind and inhibit the active sites of PPPs, they are largely non-selective, typically inhibiting one or more family members with equal potencies. Thus, the use of these toxins as chemical tools to study the relationship between individual PPPs and their biological substrates, and how disruptions in these relationships contributes to human disease, is severely limited...
November 20, 2017: Journal of the American Chemical Society
Olga Gorelenkova Miller, Kyle S Cole, Corey C Emerson, Dharmaraja Allimuthu, Marcin Golczak, Phoebe L Stewart, Eranthie Weerapana, Drew J Adams, John J Mieyal
Glutaredoxin (Grx1) is a ubiquitously expressed thiol-disulfide oxidoreductase that specifically catalyzes reduction of S-glutathionylated substrates. Grx1 is known to be a key regulator of pro-inflammatory signaling, and Grx1 silencing inhibits inflammation in inflammatory disease models. Therefore, we anticipate that inhibition of Grx1 could be an anti-inflammatory therapeutic strategy. We used a rapid screening approach to test 504 novel electrophilic compounds for inhibition of Grx1, which has a highly reactive active-site cysteine residue (pKa 3...
2017: PloS One
Caitlyn M Rotondo, Gerard D Wright
The β-lactams are the most successful class of antibiotic drugs but they are vulnerable to inactivation by a growing cadre of β-lactamases that now number more than a thousand variants. β-Lactamases operate by one of two general chemical mechanisms either catalyzing β-lactam ring hydrolysis via a covalent enzyme intermediate through the aegis of an active site serine residue or through a noncovalent Zn-dependent mechanism. The Ser-β-lactamases are currently dominant in the clinic and consequently, there has been great effort to identify inhibitors and to co-formulate these with β-lactam antibiotics...
November 15, 2017: Current Opinion in Microbiology
Sivakumar Prasanth Kumar, Chirag N Patel, Prakash C Jha, Himanshu A Pandya
The identification of isatin sulfonamide as a potent small molecule inhibitor of caspase-3 had fuelled the synthesis and characterization of the numerous sulfonamide class of inhibitors to optimize for potency. Recent works that relied on the ligand-based approaches have successfully shown the regions of optimizations for sulfonamide scaffold. We present here molecular dynamics-based pharmacophore modeling of caspase-3-isatin sulfonamide crystal structure, to elucidate the essential non-covalent contacts and its associated pharmacophore features necessary to ensure caspase-3 optimal binding...
August 9, 2017: Computational Biology and Chemistry
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