Current research in chemical biology最新文献_第2页

Expanding peptide-cucurbit[7]uril interactions through selective N-terminal reductive alkylation 通过选择性N-末端还原烷基化扩大肽-葫芦[7]脲的相互作用

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2021.100013

Rolande Meudom , Nan Zheng , Shugao Zhu , Michael T. Jacobsen , Liping Cao , Danny Hung-Chieh Chou

{"title":"Expanding peptide-cucurbit[7]uril interactions through selective N-terminal reductive alkylation","authors":"Rolande Meudom , Nan Zheng , Shugao Zhu , Michael T. Jacobsen , Liping Cao , Danny Hung-Chieh Chou","doi":"10.1016/j.crchbi.2021.100013","DOIUrl":"10.1016/j.crchbi.2021.100013","url":null,"abstract":"<div><p>Cucurbit[7]uril (CB[7]) is a supramolecular binding host for peptides and proteins with N-terminal Phe. However, the low occurrence of such peptides and proteins limits broader applications of this unique host-guest interaction. Here, we report a strategy to expand the scope of CB[7]-peptide interaction by site-specifically introducing N-terminal substitutions (e.g. benzyl groups) using reductive alkylation. N-terminal benzylated peptides have similar affinity to CB[7] as native peptides with N-terminal Phe and even stronger interactions can be achieved using better ligands. We further expanded this host-guest interaction to be stimuli responsive. By introducing benzyl carboxylate substituents, the CB[7]-peptide interaction shows pH-dependent binding. Furthermore, benzyl boronate substituents led to saccharide-dependent CB[7]-peptide interactions. We demonstrated that using this strategy to introduce stronger CB[7] binders to the N-terminus of human calcitonin (hCT) results in increased aggregation stability in the presence of CB[7]. This strategy to expand CB[7]-peptide interaction scope opens opportunities for future applications in peptides and proteins.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100013"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666246921000136/pdfft?md5=5a4f95eb3ce735ed4ef4fb538e218a4f&pid=1-s2.0-S2666246921000136-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48822778","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: 4

Comparative reactivity profiling of cysteine-specific probes by chemoproteomics 半胱氨酸特异性探针的化学蛋白质组学反应性比较

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100024

Fan Yang , Nan Chen , Fengzhang Wang , Guogeng Jia , Chu Wang

{"title":"Comparative reactivity profiling of cysteine-specific probes by chemoproteomics","authors":"Fan Yang , Nan Chen , Fengzhang Wang , Guogeng Jia , Chu Wang","doi":"10.1016/j.crchbi.2022.100024","DOIUrl":"10.1016/j.crchbi.2022.100024","url":null,"abstract":"<div><p>Cysteines, as one of the most intrinsically nucleophilic amino acids, play important roles in proteins involved in diverse biological processes. They are also targets of covalent drugs for treating cancers and other diseases. Understanding the cysteine reactivity towards different types of electrophilic reactive groups will contribute to design of cysteine-reactive probes and facilitate the development of cysteine-based covalent drugs. In this study, we systematically evaluated the cysteinome reactivity toward two common electrophilic probes that are based on nucleophilic substitution and Michael addition, respectively, using chemical proteomic strategies. Our profiling results showed that each probe had its own preferential reactivity towards different cysteines and the engagement of the ligand fragments could only be distinguished by the probe with the matching reactive group. Our study highlighted the importance of choosing proper cysteine-reactive probes for screening covalent ligands and provided informative guidance for covalent drug development.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100024"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666246922000064/pdfft?md5=0072c427d2286dd3eb5a86f75b351ce5&pid=1-s2.0-S2666246922000064-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49613605","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: 6

Phagocytosis: A (Sphingo)Lipid Story 吞噬作用:一个(鞘)脂质故事

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100030

Ojal Saharan , Neelay Mehendale , Siddhesh S. Kamat

{"title":"Phagocytosis: A (Sphingo)Lipid Story","authors":"Ojal Saharan , Neelay Mehendale , Siddhesh S. Kamat","doi":"10.1016/j.crchbi.2022.100030","DOIUrl":"10.1016/j.crchbi.2022.100030","url":null,"abstract":"<div><p>Phagocytosis is an evolutionary conserved innate immunological response, critical for fighting off pathogens and/or infections in higher organisms, including humans. During this process, any detrimental foreign particles (e.g. bacteria, virus, dead cells) are engulfed by immune cells called phagocytes (e.g. macrophages, monocytes), and packaged in an intracellular entity (or organelle) called the phagosome. The phagosome then undergoes a well-choreographed sequence of changes in protein and lipid composition termed “phagosomal maturation”, eventually fuses with the lysosome to form the phagolysosome, and thus marks the end of phagocytosis. While a lot is known of the proteomic changes during phagosomal maturation, in comparison, till recently, little remained known of the lipidomic changes during this process. Here, we review the current knowledge of the lipid changes on purified phagosomes, namely early and late phagosomes, during phagosomal maturation, with a special focus on sphingolipid metabolism during this important immune response.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100030"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266624692200012X/pdfft?md5=35c1f42f3f2a93701e1518fca4c0ed02&pid=1-s2.0-S266624692200012X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43467430","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: 2

3D QSAR and pharmacophore studies on inhibitors of insuline like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) as potential anti-cancer agents 胰岛素样生长因子1受体(IGF-1R)和胰岛素受体(IR)抑制剂作为潜在抗癌药物的3D QSAR和药效团研究

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100019

Mustafa Kamal Pasha , Ishrat Jabeen , Sandhya Samarasinghe

{"title":"3D QSAR and pharmacophore studies on inhibitors of insuline like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) as potential anti-cancer agents","authors":"Mustafa Kamal Pasha , Ishrat Jabeen , Sandhya Samarasinghe","doi":"10.1016/j.crchbi.2022.100019","DOIUrl":"https://doi.org/10.1016/j.crchbi.2022.100019","url":null,"abstract":"<div><p>Insulin like growth factor receptor (IGF-1R) and Insulin receptor (IR) are widely accepted to play a prominent role in cancer drug discovery due to their well-established involvement in various stages of tumorigenesis. Previously, neutralization of IGF-1R via monoclonal antibodies was in focus, which failed because of compensatory activation of IR-A upon inhibition of IGF-1R. Recent studies have demonstrated high homology between IGF-IR and IR particularly in tyrosine kinase domain and targeting both receptors have produced efficient therapeutic approaches such as inhibition of cancer cell cycle proliferation. Herein, we have made an attempt to analyze the unique data set from different chemical classes, containing potent ATP competitors against tyrosine kinase domain. We performed the 2D, 3D quantitative structure–activity relationship (QSAR) studies on inhibitors of these receptors to predict useful pharmacophoric features. We have optimized virtual screening of structurally diverse data set of dual inhibitors of IGF-1R and IR. Based on QSAR studies, we predict potential novel clinical candidates with a demonstrated absorption, distribution, metabolism, elimination, and toxicology (ADMETox) track. We also demonstrated comprehensive analysis of co–crystal complexes along with their inhibitors and built 3D- GRid INdependent Descriptors (GRIND) model to obtain insightful features such as H-bond donors and acceptors, overall topology and Vander Waal volume (vdw_vol) which are found to be responsible for dual inhibition of receptors. These findings lead to further description that Tirofiban, Practolol, Edoxaban, Novobiocin have potential to perform dual inhibition of both targets.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100019"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666246922000015/pdfft?md5=aa21bfa3f83f5a2a085fec440659caf1&pid=1-s2.0-S2666246922000015-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92132945","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

Discovery of diminazene as a dual inhibitor of SARS-CoV-2 human host proteases TMPRSS2 and furin using cell-based assays 使用基于细胞的检测方法发现迪米纳烯作为SARS-CoV-2人类宿主蛋白酶TMPRSS2和furin的双重抑制剂

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100023

Ya-Ming Xu, Marielle Cascaes Inacio, Manping X. Liu, A.A. Leslie Gunatilaka

{"title":"Discovery of diminazene as a dual inhibitor of SARS-CoV-2 human host proteases TMPRSS2 and furin using cell-based assays","authors":"Ya-Ming Xu, Marielle Cascaes Inacio, Manping X. Liu, A.A. Leslie Gunatilaka","doi":"10.1016/j.crchbi.2022.100023","DOIUrl":"10.1016/j.crchbi.2022.100023","url":null,"abstract":"<div><p>The proteases TMPRSS2 (transmembrane protease serine 2) and furin are known to play important roles in viral infectivity including systematic COVID-19 infection through priming of the spike protein of SARS-CoV-2 and related viruses. To discover small-molecules capable of inhibiting these host proteases, we established convenient and cost-effective cell-based assays employing Vero cells overexpressing TMPRSS2 and furin. A cell-based proteolytic assay for broad-spectrum protease inhibitors was also established using human prostate cancer cell line LNCaP. Evaluation of camostat, nafamostat, and gabexate in these cell-based assays confirmed their known TMPRSS2 inhibitory activities. Diminazene, a veterinary medicinal agent and a known furin inhibitor was found to inhibit both TMPRSS2 and furin with IC<sub>50</sub>s of 1.35 and 13.2 <em>μ</em>M, respectively. Establishment and the use of cell-based assays for evaluation TMPRSS2 and furin inhibitory activity and implications of dual activity of diminazene vs TMPRSS2 and furin are presented.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100023"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8920474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10321798","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: 4

Expanding the landscape of E3 ligases for targeted protein degradation 拓展E3连接酶用于靶向蛋白降解的领域

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100020

Luke T. Kramer , Xiaoyu Zhang

引用次数: 20

Target identification of baicalein derivative using DNA-programmed photoaffinity labeling DNA程序化光亲和标记法鉴定黄芩苷衍生物

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2021.100014

Yuxiao Tang , Xiaobin Zhuo , Yan Cao , Diya Lv , Langdong Chen , Yinyin Zhang , Jianxin Yang , Hui Shen , Xin Dong , Dongyao Wang

引用次数: 0

Stereochemical diversity as a source of discovery in chemical biology 立体化学多样性是化学生物学发现的源泉

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100028

Kevin A. Scott , Nathalie Ropek , Bruno Melillo , Stuart L. Schreiber , Benjamin F. Cravatt , Ekaterina V. Vinogradova

{"title":"Stereochemical diversity as a source of discovery in chemical biology","authors":"Kevin A. Scott , Nathalie Ropek , Bruno Melillo , Stuart L. Schreiber , Benjamin F. Cravatt , Ekaterina V. Vinogradova","doi":"10.1016/j.crchbi.2022.100028","DOIUrl":"10.1016/j.crchbi.2022.100028","url":null,"abstract":"<div><p>Chirality is an inherent aspect of biology, and interactions between biomolecules are often influenced by stereochemistry and topographic complexity. This has implications for how small-molecule libraries are assembled for screening campaigns in chemical biology and drug discovery. Here we review the state of the field in the context of harnessing chirality as a source of chemical information at the chemistry-biology interface. We further highlight the emergence of screening libraries containing stereoisomeric sets of compounds and the concept of using stereoselectivity of phenotype and/or target engagement as a way to prioritize actionable targets and streamline the identification of selective and potent modulators of disease-relevant biomolecules. The chemical information density of FDA-approved drugs and the effect of stereochemistry on molecular complexity are reported. Finally, axial chirality and atroposelectivity are discussed as potential expansions of the aforementioned concepts.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100028"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666246922000106/pdfft?md5=733064ec2b6f61b8cfa2416d0445c01b&pid=1-s2.0-S2666246922000106-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48434968","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: 10

Synergistic nitroreductase/vanadium catalysis enables chemoselective nitro reductions to anilines in the absence of hydrogen gas 协同硝基还原酶/钒催化使化学选择性硝基还原苯胺在没有氢气的情况下

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100026

Serena Bisagni , Amin Bornadel , Alan H. Cherney , Simon J. Hedley , Jacques LePaih , Steven M. Mennen , Ahir Pushpanath , Iustina Slabu , Jason Tedrow , Beatriz Dominguez

{"title":"Synergistic nitroreductase/vanadium catalysis enables chemoselective nitro reductions to anilines in the absence of hydrogen gas","authors":"Serena Bisagni , Amin Bornadel , Alan H. Cherney , Simon J. Hedley , Jacques LePaih , Steven M. Mennen , Ahir Pushpanath , Iustina Slabu , Jason Tedrow , Beatriz Dominguez","doi":"10.1016/j.crchbi.2022.100026","DOIUrl":"10.1016/j.crchbi.2022.100026","url":null,"abstract":"<div><p>Anilines are valuable synthons in pharmaceuticals and agrochemicals. These compounds are generally produced by chemocatalytic reduction of the corresponding nitrobenzene precursors. However, known synthetic methods often lack sufficient activity or selectivity, which results in low yields or the formation of a variety of undesired side products. We envisaged a biocatalytic approach as a promising general platform for selective and mild nitroarene reduction. Herein, we report using nitroreductases in combination with vanadium salts for the quantitative reduction of nitroaromatics to their corresponding anilines. Substrate scope studies were performed with fourteen nitrobenzene and four nitropyridine compounds. In one example, the reaction was intensified to 27 g/L substrate loading at 25 mL scale, where chemoselective reduction of the nitro group was obtained with full conversion and more than 93% selectivity toward aniline product (isolated in 82% yield). These conditions demonstrate the first general enzymatic method for the reduction of nitroaromatics to anilines.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100026"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666246922000088/pdfft?md5=09d9bb1b45244df02801fc53d4fc02c6&pid=1-s2.0-S2666246922000088-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49254561","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: 3

Methods for profiling the target and off-target landscape of PARP inhibitors PARP抑制剂靶区和脱靶区分析方法

Current research in chemical biology Pub Date : 2022-01-01 DOI: 10.1016/j.crchbi.2022.100027

Daniel S. Bejan, Michael S. Cohen

引用次数: 2