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https://www.readbyqxmd.com/read/29140075/strictosidine-synthase-triggered-enantioselective-synthesis-of-n-substituted-s-3-14-18-19-tetrahydroangustines-as-novel-topoisomerase-i-inhibitors
#1
Yunrui Cai, Huajian Zhu, Zaccary Alperstein, Wenjun Yu, Artem Cherkasov, Hongbin Zou
Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and these have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved Topoisomerase I (Top1) inhibitors. The enzyme STR1, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19-tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Top1 inhibition activities...
November 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29138295/generation-of-specific-inhibitors-of-sumo-1-and-sumo-2-3-mediated-protein-protein-interactions-using-affimer-adhiron-technology
#2
David J Hughes, Christian Tiede, Natalie Penswick, Anna Ah-San Tang, Chi H Trinh, Upasana Mandal, Katarzyna Z Zajac, Thembaninskosi Gaule, Gareth Howell, Thomas A Edwards, Jianxin Duan, Eric Feyfant, Michael J McPherson, Darren C Tomlinson, Adrian Whitehouse
Because protein-protein interactions underpin most biological processes, developing tools that target them to understand their function or to inform the development of therapeutics is an important task. SUMOylation is the posttranslational covalent attachment of proteins in the SUMO family (SUMO-1, SUMO-2, or SUMO-3), and it regulates numerous cellular pathways. SUMOylated proteins are recognized by proteins with SUMO-interaction motifs (SIMs) that facilitate noncovalent interactions with SUMO. We describe the use of the Affimer system of peptide display for the rapid isolation of synthetic binding proteins that inhibit SUMO-dependent protein-protein interactions mediated by SIMs both in vitro and in cells...
November 14, 2017: Science Signaling
https://www.readbyqxmd.com/read/29132113/fluorometric-detection-of-protein-ligand-engagement-the-case-of-phosphodiesterase5
#3
Giulia Di Rocco, Ilaria Martinelli, Salvatore Pacifico, Remo Guerrini, Elena Cichero, Paola Fossa, Silvia Franchini, Silvia Cardarelli, Mauro Giorgi, Marco Sola, Glauco Ponterini
Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP. The great clinical success of the PDE5 inhibitors, Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) has led to an increasing interest for this class of enzymes. Recent studies have shown a correlation between tumor growth and PDE5 overexpression, making PDE5-selective inhibitors promising candidates for cancer treatment. The search for such inhibitors rests today on radioactive assays. In this work, we exploit the conserved catalytic domain of the enzyme and propose a faster and safer method for detecting the binding of ligands and evaluate their affinities...
November 10, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29131621/expanding-the-armory-predicting-and-tuning-covalent-warhead-reactivity
#4
Richard Lonsdale, Jonathan Burgess, Nicola Colclough, Nichola L Davies, Eva M Lenz, Alexandra Orton, Richard A Ward
Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or 'warhead'). Structural changes that increase or decrease warhead reactivity, guided by methods to predict the effect of those changes, have the potential to tune warhead reactivity and negate issues related to potency and/or toxicity...
November 13, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29129599/itk-and-rlk-inhibitor-prn694-improves-skin-disease-in-two-mouse-models-of-psoriasis
#5
Jessica M Fuhriman, Mårten C G Winge, Helena Haberstock-Debic, Jens Oliver Funk, J Michael Bradshaw, M Peter Marinkovich
The chronic and highly prevalent skin disorder psoriasis vulgaris is characterized by a hyperproliferative epidermis and aberrant immune activity. Many studies have highlighted the role of differentiated T lymphocytes in psoriasis progression. Several biologics are currently available that target pro-inflammatory cytokines produced by T-lymphocytes, but the need for improved therapies persists. The small molecule PRN694 covalently binds ITK and RLK, two TEC kinases activated downstream of T lymphocyte activation, both of which are upregulated in psoriatic skin...
November 9, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29124976/rethinking-mercury-the-role-of-selenium-in-the-pathophysiology-of-mercury-toxicity
#6
Henry A Spiller
INTRODUCTION: There is increasing evidence that the pathophysiological target of mercury is in fact selenium, rather than the covalent binding of mercury to sulfur in the body's ubiquitous sulfhydryl groups. The role of selenium in mercury poisoning is multifaceted, bidirectional, and central to understanding the target organ toxicity of mercury. METHODS: An initial search was performed using Medline/PubMed, Toxline, Google Scholar, and Google for published work on mercury and selenium...
November 10, 2017: Clinical Toxicology
https://www.readbyqxmd.com/read/29124934/can-relative-binding-free-energy-predict-selectivity-of-reversible-covalent-inhibitors
#7
Payal Chatterjee, Wesley M Botello-Smith, Han Zhang, Li Qian, Abdelaziz Alsamarah, David Kent, Jerome J Lacroix, Michel Baudry, Yun Luo
Reversible covalent inhibitors have many clinical advantages over noncovalent or covalent drugs. However, apart from selecting a warhead, substantial efforts in design and synthesis are needed to optimize noncovalent interactions to improve target-selective binding. Computational prediction of binding affinity for reversible covalent inhibitors presents a unique challenge since the binding process consists of multiple steps, which are not necessarily independent of each other. In this study, we lay out the relation between relative binding free energy and the overall reversible covalent binding affinity using a two-state binding model...
November 10, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29123089/tsg101-chaperone-function-revealed-by-hiv-1-assembly-inhibitors
#8
Madeleine Strickland, Lorna S Ehrlich, Susan Watanabe, Mahfuz Khan, Marie-Paule Strub, Chi-Hao Luan, Michael D Powell, Jonathan Leis, Nico Tjandra, Carol A Carter
HIV-1 replication requires Tsg101, a component of cellular endosomal sorting complex required for transport (ESCRT) machinery. Tsg101 possesses an ubiquitin (Ub) E2 variant (UEV) domain with a pocket that can bind PT/SAP motifs and another pocket that can bind Ub. The PTAP motif in the viral structural precursor polyprotein, Gag, allows the recruitment of Tsg101 and other ESCRTs to virus assembly sites where they mediate budding. It is not known how or even whether the UEV Ub binding function contributes to virus production...
November 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/29119993/a-study-of-the-reactivity-of-s-vi-f-containing-warheads-with-nucleophilic-amino-acid-side-chains-under-physiological-conditions
#9
H Mukherjee, J Debreczeni, J Breed, S Tentarelli, B Aquila, J E Dowling, A Whitty, N P Grimster
Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related S(VI)-F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues...
November 9, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29116686/protocols-for-the-design-of-kinase-focused-compound-libraries
#10
Edgar Jacoby, Berthold Wroblowski, Christophe Buyck, Jean-Marc Neefs, Christophe Meyer, Maxwell D Cummings, Herman van Vlijmen
Protocols for the design of kinase-focused compound libraries are presented. Kinase-focused compound libraries can be differentiated based on the design goal. Depending on whether the library should be a discovery library specific for one particular kinase, a general discovery library for multiple distinct kinase projects, or even phenotypic screening, there exists today a variety of in silico methods to design candidate compound libraries. We address the following scenarios: 1) Datamining of SAR databases and kinase focused vendor catalogues; 2) Predictions and virtual screening; 3) Structure-based design of combinatorial kinase inhibitors; 4) Design of covalent kinase inhibitors; 5) Design of macrocyclic kinase inhibitors; and 6) Design of allosteric kinase inhibitors and activators...
November 8, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/29114958/evidence-for-multiple-modes-of-neutrophil-serine-protease-recognition-by-the-eap-family-of-staphylococcal-innate-immune-evasion-proteins
#11
Daphne A C Stapels, Jordan L Woehl, Fin J Milder, Angelino T Tromp, Aernoud A van Batenburg, Wilco C de Graaf, Samuel C Broll, Natalie M White, Suzan H M Rooijakkers, Brian V Geisbrecht
Neutrophils contain high levels of chymotrypsin-like serine proteases (NSPs) within their azurophilic granules that have a multitude of functions within the immune system. In response, the pathogen Staphylococcus aureus has evolved three potent inhibitors (Eap, EapH1, and EapH2) that protect the bacterium as well as several of its secreted virulence factors from the degradative action of NSPs. We previously showed that these so-called EAP domain proteins represent a novel class of NSP inhibitors characterized by a non-covalent inhibitory mechanism and a distinct target specificity profile...
November 7, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29109275/engineering-of-a-membrane-triggered-activity-switch-in-coagulation-factor-viia
#12
Anders L Nielsen, Anders B Sorensen, Heidi L Holmberg, Prafull S Gandhi, Johan Karlsson, Jens Buchardt, Kasper Lamberth, Mads Kjelgaard-Hansen, Carsten Dan Ley, Brit B Sørensen, Wolfram Ruf, Ole H Olsen, Henrik Østergaard
Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects...
November 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29107765/ncp7-targeting-a-multitasking-protein-for-next-generation-anti-hiv-drug-development-covalent-inhibitors
#13
REVIEW
Luca Sancineto, Nunzio Iraci, Oriana Tabarrini, Claudio Santi
The major internal component of the HIV virion core is the nucleocapsid protein 7 (NCp7), a small, highly basic protein that is essential for multiple stages of the viral replicative cycle, and whose structure is preserved in all viral strains, including clinical isolates from therapy-experienced patients. This key protein is recognised as a potential target for an effective next-generation antiretroviral therapy, because it could offer the possibility to develop broad-spectrum agents that are less prone to select for resistant strains...
October 28, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/29107700/general-and-modular-strategy-for-designing-potent-selective-and-pharmacologically-compliant-inhibitors-of-rhomboid-proteases
#14
Anežka Tichá, Stancho Stanchev, Kutti R Vinothkumar, David C Mikles, Petr Pachl, Jakub Began, Jan Škerle, Kateřina Švehlová, Minh T N Nguyen, Steven H L Verhelst, Darren C Johnson, Daniel A Bachovchin, Martin Lepšík, Pavel Majer, Kvido Strisovsky
Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude...
October 12, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29091392/thiol-benzo-triazolo-quinazolinone-covalently-modifies-alg44-to-inhibit-c-di-gmp-binding-and-reduces-alginate-production-by-pseudomonas-aeruginosa
#15
Eric Zhou, Anna B Seminara, Soo-Kyoung Kim, Cherisse L Hall, Yan Wang, Vincent T Lee
Pseudomonas aeruginosa is an opportunistic pathogen that affects a large proportion of cystic fibrosis (CF) patients. CF patients have dehydrated mucus within the airways that leads to the inability of the mucociliary escalator to expel inhaled microbes. Once inhaled, P. aeruginosa can persist in the lungs of the CF patients for the remainder of their lives. During this chronic infection, a phenomenon called mucoid conversion can occur in which P. aeruginosa can mutate and inactivate their mucA gene. As a consequence, transcription of the alg operon is highly expressed leading to the copious secretion of the alginate exopolysaccharide, which is associated with decreased lung function and increased CF patient morbidity and mortality...
November 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29073621/sexually-dimorphic-epigenetic-regulation-of-brain-derived-neurotrophic-factor-in-fetal-brain-in-the-valproic-acid-model-of-autism-spectrum-disorder
#16
Melissa A Konopko, Allison L Densmore, Bruce K Krueger
Prenatal exposure to the antiepileptic, mood-stabilizing drug, valproic acid (VPA), increases the incidence of autism spectrum disorders (ASDs); in utero administration of VPA to pregnant rodents induces ASD-like behaviors such as repetitive, stereotyped activity, and decreased socialization. In both cases, males are more affected than females. We previously reported that VPA, administered to pregnant mice at gestational day 12.5, rapidly induces a transient, 6-fold increase in BDNF (brain-derived neurotrophic factor) protein and mRNA in the fetal brain...
October 27, 2017: Developmental Neuroscience
https://www.readbyqxmd.com/read/29070414/following-the-lead-from-nature-with-covalent-inhibitors
#17
Roman Lagoutte, Nicolas Winssinger
Covalent inhibitors are re-emerging as pharmacologically interesting entities with several candidates having received recent approval for therapeutic intervention. Nature has embraced this strategy and many natural products possess mildly electrophilic moieties able to covalently engage a target protein. This review surveys recent case studies for the identification of the target proteins of natural products. While sesquiterpene lactones represent a vast repertoire of covalent inhibitors, they can also be found in other classes of natural products, with sometimes unusual mechanisms to unmask the electrophilic moieties...
October 25, 2017: Chimia
https://www.readbyqxmd.com/read/29068682/activity-based-probes-for-isoenzyme-and-site-specific-functional-characterization-of-glutathione-s-transferases
#18
Ethan G Stoddard, Bryan J Killinger, Reji N Nair, Natalie C Sadler, Regan F Volk, Samuel O Purvine, Anil K Shukla, Jordan N Smith, Aaron T Wright
Glutathione S-transferases (GSTs) comprise a diverse family of phase II drug metabolizing enzymes whose shared function is the conjugation of reduced glutathione (GSH) to endo- and xenobiotics. Although the conglomerate activity of these enzymes can be measured, the isoform-specific contribution to the metabolism of xenobiotics in complex biological samples has not been possible. We have developed two activity-based probes (ABPs) that characterize active GSTs in mammalian tissues. The GST active site is composed of a GSH binding "G site" and a substrate binding "H site"...
November 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29065764/recognition-and-stabilization-of-geranylgeranylated-human-rab5-by-the-gdp-dissociation-inhibitor-gdi
#19
Eileen Edler, Matthias Stein
The small GTPase Rab5 is the key regulator of early endosomal fusion. It is post-translationally modified by covalent attachment of two geranylgeranyl (GG) chains to adjacent cysteine residues of the C-terminal hypervariable region (HVR). The GDP dissociation inhibitor (GDI) recognizes membrane-associated Rab5(GDP) and serves to release it into the cytoplasm where it is kept in a soluble state. A detailed new structural and dynamic model for human Rab5(GDP) recognition and binding with human GDI at the early endosome membrane and in its dissociated state is presented...
October 25, 2017: Small GTPases
https://www.readbyqxmd.com/read/29057062/discovery-of-mechanism-based-inactivators-for-human-pancreatic-carboxypeptidase-a-from-a-focused-synthetic-library
#20
Sebastián A Testero, Carla Granados, Daniel Fernández, Pablo Gallego, Giovanni Covaleda, David Reverter, Josep Vendrell, Francesc X Avilés, Irantzu Pallarès, Shahriar Mobashery
Metallocarboxypeptidases (MCPs) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site...
October 12, 2017: ACS Medicinal Chemistry Letters
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