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Covalent inhibitors

Jiankang Zhang, Lixin Gao, Jianjun Xi, Li Sheng, Yanmei Zhao, Lei Xu, Yidan Shao, Shourong Liu, Rangxiao Zhuang, Yubo Zhou, Jia Li
A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20nM, and four are more potent than the positive control Carfilzomib...
October 6, 2016: Bioorganic & Medicinal Chemistry
Carmine Carbone, Elena Di Gennaro, Geny Piro, Maria Rita Milone, Biagio Pucci, Michele Caraglia, Alfredo Budillon
Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca(2+) dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential...
October 19, 2016: Amino Acids
Kenichi Morikawa, Tomoe Shimazaki, Rei Takeda, Takaaki Izumi, Machiko Umumura, Naoya Sakamoto
Hepatitis B virus (HBV) infection is a serious health threat around the world. Despite the availability of an effective hepatitis B vaccine, the number of HBV carriers is estimated to be as high as 240 million worldwide. Global mortality due to HBV-related liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) may be as high as 1 million deaths per year. HBV is transmitted via blood and body fluids, and is much more infectious than both human immunodeficiency virus (HIV) and hepatitis C virus...
September 2016: Annals of Translational Medicine
John E Cebak, Indrapal N Singh, Rachel L Hill, Juan Wang, Edward D Hall
Lipid peroxidation is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either the initiation or the propagation of lipid peroxidation (LP). A more recently explored approach involves scavenging the terminal LP breakdown products that are highly reactive and neurotoxic carbonyl compounds 4-hydroxynonenal (4-HNE) and acrolein to prevent their covalent modification and rendering of cellular proteins non-functional leading to loss of ionic homeostasis, mitochondrial failure, and subsequent neuronal death...
October 18, 2016: Journal of Neurotrauma
Qiong Xiao, Qin Yin, Hui Ni, Huinong Cai, Changzheng Wu, Anfeng Xiao
Carboxyl functioned magnetic nanoparticles (CMNPs) were prepared by a simple co-precipitation method and characterized by Fourier transform infrared spedtroscopy and scanning electron microscope. The prepared CMNPs were used for covalent immobilization of the arylsulfatase which could be applied in desulfation of agar. The optimal immobilizaion conditions were obtained as follows: glutaraldehyde concentration 1.0% (v/v), cross-linking time 3h, immobilization time 3h, immobilization temperature 5°C and enzyme dose 0...
October 13, 2016: International Journal of Biological Macromolecules
Maarten Danial, Angela Stauffer, Frederik R Wurm, Michael J Root, Harm-Anton Klok
A popular strategy to overcome the limited plasma half-life of peptide heptad repeat 2 (HR2) fusion inhibitors against HIV-1 is through conjugation with biocompatible polymers such as poly(ethylene glycol) (PEG). However, despite improved resistance to proteolysis and reduced renal elimination, covalent attachment of polymers often causes a loss in therapeutic potency. In this study, we investigated the molecular origins of the loss in potency upon conjugation of linear, mid-functional and hyperbranched PEG-like polymers to peptides that inhibit HIV-1 - host cell membrane fusion...
October 13, 2016: Bioconjugate Chemistry
Adriana Ariza, Cristobalina Mayorga, María Salas, Inmaculada Doña, Ángela Martín-Serrano, Ezequiel Pérez-Inestrosa, Dolores Pérez-Sala, Antonio E Guzmán, María I Montañez, María J Torres
The optimal recognition of penicillin determinants, including amoxicillin (AX), by specific IgE antibodies is widely believed to require covalent binding to a carrier molecule. The nature of the carrier and its contribution to the antigenic determinant is not well known. Here we aimed to evaluate the specific-IgE recognition of different AX-derived structures. We studied patients with immediate hypersensitivity reactions to AX, classified as selective or cross-reactors to penicillins. Competitive immunoassays were performed using AX itself, amoxicilloic acid, AX bound to butylamine (AXO-BA) or to human serum albumin (AXO-HSA) in the fluid phase, as inhibitors, and amoxicilloyl-poli-L-lysine (AXO-PLL) in the solid-phase...
October 12, 2016: Scientific Reports
Steven K Montalvo, Lianbo Li, Kenneth D Westover
RAS mutations are among the most common genetic alterations found in cancerous tumors but rational criteria or strategies for targeting RAS-dependent tumors are only recently emerging. Clinical and laboratory data suggest that patient selection based on specific RAS mutations will be an essential component of these strategies. A thorough understanding of the biochemical and structural properties of mutant RAS proteins form the theoretical basis for these approaches. Direct inhibition of KRAS G12C by covalent inhibitors is a notable recent example of the RAS mutation-tailored approach that establishes a paradigm for other RAS mutation-centered strategies...
October 12, 2016: Future Oncology
Nidal E Muvarak, Khadiza Chowdhury, Limin Xia, Carine Robert, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Zeba N Singh, Vu H Duong, Tyler Rutherford, Pratik Nagaria, Søren M Bentzen, Michael M Seidman, Maria R Baer, Rena G Lapidus, Stephen B Baylin, Feyruz V Rassool
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites...
October 10, 2016: Cancer Cell
Jun Ando, Miwako Asanuma, Kosuke Dodo, Hiroyuki Yamakoshi, Satoshi Kawata, Katsumasa Fujita, Mikiko Sodeoka
Identification of small-molecule-binding sites in protein is important for drug discovery and analysis of protein function. Modified amino-acid residue(s) can be identified by proteolytic cleavage followed by liquid chromatography-mass spectrometry (LC-MS), but this is often hindered by the complexity of the peptide mixtures. We have developed alkyne-tag Raman screening (ATRaS) for identifying binding sites. In ATRaS, small molecules are tagged with alkyne and form covalent bond with proteins. After proteolysis and HPLC, fractions containing the labeled peptides with alkyne tags are detected by means of surface-enhanced Raman scattering (SERS) using silver nanoparticles and sent to MS/MS to identify the binding site...
October 10, 2016: Journal of the American Chemical Society
Lei Wang
The genetic code can be expanded to include unnatural amino acids (Uaas) by engineering orthogonal components involved in protein translation. To be compatible with live cells, side chains of Uaas have been limited to either chemically inert or bio-orthogonal (i.e., nonreactive toward biomolecules) functionalities. To introduce bioreactivity into live systems, the genetic code has recently been engineered to encode a new class of Uaas, the bioreactive Uaas. These Uaas, after being incorporated into proteins, specifically react with target natural amino acid residues via proximity-enabled bioreactivity, enabling the selective formation of new covalent linkages within and between proteins both in vitro and in live systems...
October 6, 2016: New Biotechnology
Natalia M Villarreal, María Marina, Cristina F Nardi, Pedro M Civello, Gustavo A Martínez
Due to its organoleptic and nutraceutical qualities, strawberry fruit (Fragaria x ananassa, Duch) is a worldwide important commodity. The role of ethylene in the regulation of strawberry cell wall metabolism was studied in fruit from Toyonoka cultivar harvested at white stage, when most changes associated with fruit ripening have begun. Fruit were treated with ethephon, an ethylene-releasing reagent, or with 1-methylcyclopropene (1-MCP), a competitive inhibitor of ethylene action, maintaining a set of non-treated fruit as controls for each condition...
November 2016: Plant Science: An International Journal of Experimental Plant Biology
Jisoo Shin, Jung Ho Cho, Yoonhee Jin, Kisuk Yang, Jong Seung Lee, Hyun-Ji Park, Hyung-Seop Han, Jinkyu Lee, Hojeong Jeon, Heungsoo Shin, Seung-Woo Cho
Using small interfering RNA (siRNA) to regulate gene expression is an emerging strategy for stem cell manipulation to improve stem cell therapy. However, conventional methods of siRNA delivery into stem cells based on solution-mediated transfection are limited due to low transfection efficiency and insufficient duration of cell-siRNA contact during lengthy culturing protocols. To overcome these limitations, a bio-inspired polymer-mediated reverse transfection system is developed consisting of implantable poly(lactic-co-glycolic acid) (PLGA) scaffolds functionalized with siRNA-lipidoid nanoparticle (sLNP) complexes via polydopamine (pDA) coating...
September 26, 2016: Small
Trinayan Kashyap, Christian Argueta, Amro Aboukameel, Thaddeus John Unger, Boris Klebanov, Ramzi M Mohammad, Irfana Muqbil, Asfar S Azmi, Claire Drolen, William Senapedis, Margaret Lee, Michael Kauffman, Sharon Shacham, Yosef Landesman
The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells...
October 4, 2016: Oncotarget
Huaqun Zhang, Cameron McGlone, Matthew M Mannion, Richard C Page
The ubiquitin ligase CHIP catalyzes covalent attachment of ubiquitin to unfolded proteins chaperoned by the heat shock proteins Hsp70/Hsc70 and Hsp90. CHIP interacts with Hsp70/Hsc70 and Hsp90 by binding of a C-terminal IEEVD motif found in Hsp70/Hsc70 and Hsp90 to the tetratricopeptide repeat (TPR) domain of CHIP. Although recruitment of heat shock proteins to CHIP via interaction with the CHIP-TPR domain is well established, alterations in structure and dynamics of CHIP upon binding are not well understood...
October 5, 2016: Biomolecular NMR Assignments
Kavya Ramkumar, Soma Samanta, Anahita Kyani, Suhui Yang, Shuzo Tamura, Elizabeth Ziemke, Jeanne A Stuckey, Si Li, Krishnapriya Chinnaswamy, Hiroyuki Otake, Bikash Debnath, Vladimir Yarovenko, Judith S Sebolt-Leopold, Mats Ljungman, Nouri Neamati
Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology. We report on the development and characterization of a series of chloroacetamide-containing potent GSTO1 inhibitors. Co-crystal structures of GSTO1 with our inhibitors demonstrate covalent binding to the active site cysteine...
October 5, 2016: Nature Communications
John M Strelow
The clinical and commercial success of covalent drugs has prompted a renewed and more deliberate pursuit of covalent and irreversible mechanisms within drug discovery. A covalent mechanism can produce potent inhibition in a biochemical, cellular, or in vivo setting. In many cases, teams choose to focus on the consequences of the covalent event, defined by an IC50 value. In a biochemical assay, the IC50 may simply reflect the target protein concentration in the assay. What has received less attention is the importance of the rate of covalent modification, defined by kinact/KI The kinact/KI is a rate constant describing the efficiency of covalent bond formation resulting from the potency (KI) of the first reversible binding event and the maximum potential rate (kinact) of inactivation...
October 4, 2016: Journal of Biomolecular Screening
Lisa Rank, Sebastian Veith, Eva C Gwosch, Janine Demgenski, Magdalena Ganz, Marjolijn C Jongmans, Christopher Vogel, Arthur Fischbach, Stefanie Buerger, Jan M F Fischer, Tabea Zubel, Anna Stier, Christina Renner, Michael Schmalz, Sascha Beneke, Marcus Groettrup, Roland P Kuiper, Alexander Bürkle, Elisa Ferrando-May, Aswin Mangerich
Genotoxic stress activates PARP1, resulting in the post-translational modification of proteins with poly(ADP-ribose) (PAR). We genetically deleted PARP1 in one of the most widely used human cell systems, i.e. HeLa cells, via TALEN-mediated gene targeting. After comprehensive characterization of these cells during genotoxic stress, we analyzed structure-function relationships of PARP1 by reconstituting PARP1 KO cells with a series of PARP1 variants. Firstly, we verified that the PARP1\E988K mutant exhibits mono-ADP-ribosylation activity and we demonstrate that the PARP1\L713F mutant is constitutively active in cells...
September 29, 2016: Nucleic Acids Research
Annemie Prové, Luc Dirix
Neratinib is an orally available, pan-HER inhibitor with clinical activity in patients with HER2-amplified and HER2-mutated breast cancer. Areas Covered. A summary of publically available and relevant clinical data on neratinib. Expert Opinion. Neratinib (N) is clearly distinct from lapatinib (L), a difference based on its broad anti-HER effect, its covalent target binding and its toxicity profile. The main toxicity of neratinib is gastro-intestinal and is essentially limited to diarrhea. Although not directly compared with single agent lapatinib, skin toxicity is much less pronounced with N...
October 3, 2016: Expert Opinion on Pharmacotherapy
Kevin Doyle, Hans Lönn, Helena Käck, Amanda Van de Poël, Steve Swallow, Philip Gardiner, Stephen Connolly, James Root, Cecilia Wikell, Göran Dahl, Kristina Stenvall, Petra Johannesson
A novel series of second generation DPP1 inhibitors free from aorta binding liabilities found for earlier compound series was discovered. This work culminated in the identification of compound 30 (AZD7986), as a highly potent, reversible and selective clinical candidate for COPD, with predicted human PK properties suitable for once daily human dosing.
October 2, 2016: Journal of Medicinal Chemistry
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