Chemistry & biology最新文献_第10页

Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus. 一氧化氮合酶作为耐甲氧西林金黄色葡萄球菌的靶点。

Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.05.013

Jeffrey K Holden, Soosung Kang, Federico C Beasley, Maris A Cinelli, Huiying Li, Saurabh G Roy, Dillon Dejam, Aimee L Edinger, Victor Nizet, Richard B Silverman, Thomas L Poulos

{"title":"Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus.","authors":"Jeffrey K Holden, Soosung Kang, Federico C Beasley, Maris A Cinelli, Huiying Li, Saurabh G Roy, Dillon Dejam, Aimee L Edinger, Victor Nizet, Richard B Silverman, Thomas L Poulos","doi":"10.1016/j.chembiol.2015.05.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.013","url":null,"abstract":"Bacterial infections associated with methicillin-resistant Staphylococcus aureus (MRSA) are a major economic burden to hospitals, and confer high rates of morbidity and mortality among those infected. Exploitation of novel therapeutic targets is thus necessary to combat this dangerous pathogen. Here, we report on the identification and characterization, including crystal structures, of two nitric oxide synthase (NOS) inhibitors that function as antimicrobials against MRSA. These data provide the first evidence that bacterial NOS (bNOS) inhibitors can work synergistically with oxidative stress to enhance MRSA killing. Crystal structures show that each inhibitor contacts an active site Ile residue in bNOS that is Val in the mammalian NOS isoforms. Mutagenesis studies show that the additional nonpolar contacts provided by the Ile in bNOS contribute to tighter binding toward the bacterial enzyme. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33283256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

Dialing in EGFR Signaling. 接入EGFR信令。

Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.06.001

Eileen J Kennedy, Natarajan Kannan

引用次数: 0

Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions. 克服针对蛋白质-蛋白质相互作用的抑制剂开发过程中的化学、生物和计算挑战。

Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.04.019

Luca Laraia, Grahame McKenzie, David R Spring, Ashok R Venkitaraman, David J Huggins

{"title":"Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions.","authors":"Luca Laraia, Grahame McKenzie, David R Spring, Ashok R Venkitaraman, David J Huggins","doi":"10.1016/j.chembiol.2015.04.019","DOIUrl":"10.1016/j.chembiol.2015.04.019","url":null,"abstract":"Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33277769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration. hRAD51化学调节对HIV-1整合的双重和相反作用。

Chemistry & biology Pub Date : 2015-06-18 Epub Date: 2015-06-04 DOI: 10.1016/j.chembiol.2015.04.020

Sylvain Thierry, Mohamed Salah Benleulmi, Ludivine Sinzelle, Eloise Thierry, Christina Calmels, Stephane Chaignepain, Pierre Waffo-Teguo, Jean-Michel Merillon, Brian Budke, Jean-Max Pasquet, Simon Litvak, Angela Ciuffi, Patrick Sung, Philip Connell, Ilona Hauber, Joachim Hauber, Marie-Line Andreola, Olivier Delelis, Vincent Parissi

{"title":"Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration.","authors":"Sylvain Thierry, Mohamed Salah Benleulmi, Ludivine Sinzelle, Eloise Thierry, Christina Calmels, Stephane Chaignepain, Pierre Waffo-Teguo, Jean-Michel Merillon, Brian Budke, Jean-Max Pasquet, Simon Litvak, Angela Ciuffi, Patrick Sung, Philip Connell, Ilona Hauber, Joachim Hauber, Marie-Line Andreola, Olivier Delelis, Vincent Parissi","doi":"10.1016/j.chembiol.2015.04.020","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.04.020","url":null,"abstract":"The cellular DNA repair hRAD51 protein has been shown to restrict HIV-1 integration both in vitro and in vivo. To investigate its regulatory functions, we performed a pharmacological analysis of the retroviral integration modulation by hRAD51. We found that, in vitro, chemical activation of hRAD51 stimulates its integration inhibitory properties, whereas inhibition of hRAD51 decreases the integration restriction, indicating that the modulation of HIV-1 integration depends on the hRAD51 recombinase activity. Cellular analyses demonstrated that cells exhibiting high hRAD51 levels prior to de novo infection are more resistant to integration. On the other hand, when hRAD51 was activated during integration, cells were more permissive. Altogether, these data establish the functional link between hRAD51 activity and HIV-1 integration. Our results highlight the multiple and opposite effects of the recombinase during integration and provide new insights into the cellular regulation of HIV-1 replication. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.04.020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33368274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Distinct Substrate Specificity and Catalytic Activity of the Pseudoglycosyltransferase VldE. 假糖基转移酶VldE的底物特异性和催化活性。

Chemistry & biology Pub Date : 2015-06-18 Epub Date: 2015-06-04 DOI: 10.1016/j.chembiol.2015.04.021

Hatem A Abuelizz, Taifo Mahmud

引用次数: 9

Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release. 在变构药物结合位点抑制amp活化蛋白激酶促进胰岛胰岛素释放。

Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.05.011

John W Scott, Sandra Galic, Kate L Graham, Richard Foitzik, Naomi X Y Ling, Toby A Dite, Samah M A Issa, Chris G Langendorf, Qing Ping Weng, Helen E Thomas, Thomas W Kay, Neal C Birnberg, Gregory R Steinberg, Bruce E Kemp, Jonathan S Oakhill

{"title":"Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release.","authors":"John W Scott, Sandra Galic, Kate L Graham, Richard Foitzik, Naomi X Y Ling, Toby A Dite, Samah M A Issa, Chris G Langendorf, Qing Ping Weng, Helen E Thomas, Thomas W Kay, Neal C Birnberg, Gregory R Steinberg, Bruce E Kemp, Jonathan S Oakhill","doi":"10.1016/j.chembiol.2015.05.011","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.011","url":null,"abstract":"The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the β2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of β2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by β1/β2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a β2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33277768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 52

Iterative Mechanism of Macrodiolide Formation in the Anticancer Compound Conglobatin. 抗癌化合物组合蛋白中大二烯内酯形成的迭代机制。

Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.05.010

Yongjun Zhou, Annabel C Murphy, Markiyan Samborskyy, Patricia Prediger, Luiz Carlos Dias, Peter F Leadlay

{"title":"Iterative Mechanism of Macrodiolide Formation in the Anticancer Compound Conglobatin.","authors":"Yongjun Zhou, Annabel C Murphy, Markiyan Samborskyy, Patricia Prediger, Luiz Carlos Dias, Peter F Leadlay","doi":"10.1016/j.chembiol.2015.05.010","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.010","url":null,"abstract":"Conglobatin is an unusual C2-symmetrical macrodiolide from the bacterium Streptomyces conglobatus with promising antitumor activity. Insights into the genes and enzymes that govern both the assembly-line production of the conglobatin polyketide and its dimerization are essential to allow rational alterations to be made to the conglobatin structure. We have used a rapid, direct in vitro cloning method to obtain the entire cluster on a 41-kbp fragment, encoding a modular polyketide synthase assembly line. The cloned cluster directs conglobatin biosynthesis in a heterologous host strain. Using a model substrate to mimic the conglobatin monomer, we also show that the conglobatin cyclase/thioesterase acts iteratively, ligating two monomers head-to-tail then re-binding the dimer product and cyclizing it. Incubation of two different monomers with the cyclase produces hybrid dimers and trimers, providing the first evidence that conglobatin analogs may in future become accessible through engineering of the polyketide synthase. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33277770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 60

Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency. 钴(III)原卟啉激活DGCR8蛋白并补偿microRNA加工缺陷。

Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.05.015

Ian Barr, Sara H Weitz, Talia Atkin, PeiKen Hsu, Maria Karayiorgou, Joseph A Gogos, Shimon Weiss, Feng Guo

{"title":"Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency.","authors":"Ian Barr, Sara H Weitz, Talia Atkin, PeiKen Hsu, Maria Karayiorgou, Joseph A Gogos, Shimon Weiss, Feng Guo","doi":"10.1016/j.chembiol.2015.05.015","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.015","url":null,"abstract":"Processing of microRNA primary transcripts (pri-miRNAs) is highly regulated and defects in the processing machinery play a key role in many human diseases. In 22q11.2 deletion syndrome (22q11.2DS), heterozygous deletion of DiGeorge critical region gene 8 (DGCR8) causes a processing deficiency, which contributes to abnormal brain development. The DGCR8 protein is the RNA-binding partner of Drosha RNase, both essential for processing canonical pri-miRNAs. To identify an agent that can compensate reduced DGCR8 expression, we screened for metalloporphyrins that can mimic the natural DGCR8 heme cofactor. We found that Co(III) protoporphyrin IX (PPIX) stably binds DGCR8 and activates it for pri-miRNA processing in vitro and in HeLa cells. Importantly, treating cultured Dgcr8(+/-) mouse neurons with Co(III)PPIX can compensate the pri-miRNA processing defects. Co(III)PPIX is effective at concentrations as low as 0.2 μM and is not degraded by heme degradation enzymes, making it useful as a research tool and a potential therapeutic. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33283257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 12

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. 劫持E3泛素连接酶小脑有效靶向BRD4

Chemistry & biology Pub Date : 2015-06-18 Epub Date: 2015-06-04 DOI: 10.1016/j.chembiol.2015.05.009

Jing Lu, Yimin Qian, Martha Altieri, Hanqing Dong, Jing Wang, Kanak Raina, John Hines, James D Winkler, Andrew P Crew, Kevin Coleman, Craig M Crews

{"title":"Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.","authors":"Jing Lu, Yimin Qian, Martha Altieri, Hanqing Dong, Jing Wang, Kanak Raina, John Hines, James D Winkler, Andrew P Crew, Kevin Coleman, Craig M Crews","doi":"10.1016/j.chembiol.2015.05.009","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.009","url":null,"abstract":"BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors. ","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33368275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 729

Cooperation for Better Inhibiting. 合作更好地抑制。

Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.06.002

Eva Maria Novoa, Lluís Ribas de Pouplana

引用次数: 3