RSC Chemical Biology最新文献_第9页

Miltefosine impacts small molecule transport in Gram-positive bacteria† 米替福新影响革兰氏阳性菌的小分子转运

IF 4.2

RSC Chemical Biology Pub Date : 2024-07-08 DOI: 10.1039/D4CB00106K

Marea J. Blake, Eleanor F. Page, Madeline E. Smith and Tessa R. Calhoun

{"title":"Miltefosine impacts small molecule transport in Gram-positive bacteria†","authors":"Marea J. Blake, Eleanor F. Page, Madeline E. Smith and Tessa R. Calhoun","doi":"10.1039/D4CB00106K","DOIUrl":"10.1039/D4CB00106K","url":null,"abstract":"Miltefosine (MLT) is an alkylphosphocholine with clinical success as an anticancer and antiparasitic drug. Although the mechanism of action of MLT is highly debated, the interaction of MLT with the membrane, specifically lipid rafts of eukaryotes, is well-documented. Recent reports suggest MLT impacts the functional membrane microdomains in bacteria – regions of the membrane structurally and functionally similar to lipid rafts. There have been conflicting reports, however, as to whether MLT impacts the overall fluidity of cellular plasma membranes. Here, we apply steady-state fluorescence techniques, generalized polarization of laurdan and anisotropy of diphenylhexatriene, to discern how MLT impacts the global ordering and lipid packing of Staphylococcus aureus membranes. Additionally, we investigate how the transport of a range of small molecules is impacted by MLT for S. aureus and Bacillus subtilis by employing time-resolved second harmonic scattering. Overall, we observe MLT does not have an influence on the overall ordering and packing of S. aureus membranes. Additionally, we show that the transport of small molecules across the membrane can be significantly altered by MLT – although this is not the case for all molecules studied. The results presented here illustrate the potential use of MLT as an adjuvant to assist in the delivery of drug molecules in bacteria.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 10","pages":" 981-988"},"PeriodicalIF":4.2,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00106k?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141567821","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

Selection and characterization of a peptide-based complement modulator targeting C1 of the innate immune system† 以先天性免疫系统 C1 为目标的肽基补体调节剂的筛选和表征

IF 4.2

RSC Chemical Biology Pub Date : 2024-07-01 DOI: 10.1039/D4CB00081A

Sebastiaan M.W.R. Hamers, Leoni Abendstein, Aimee L. Boyle, Seino A.K. Jongkees and Thomas H. Sharp

{"title":"Selection and characterization of a peptide-based complement modulator targeting C1 of the innate immune system†","authors":"Sebastiaan M.W.R. Hamers, Leoni Abendstein, Aimee L. Boyle, Seino A.K. Jongkees and Thomas H. Sharp","doi":"10.1039/D4CB00081A","DOIUrl":"10.1039/D4CB00081A","url":null,"abstract":"The human complement pathway plays a pivotal role in immune defence, homeostasis, and autoimmunity regulation, and complement-based therapeutics have emerged as promising interventions, with both antagonistic and agonistic approaches being explored. The classical pathway of complement is initiated when the C1 complex binds to hexameric antibody platforms. Recent structural data revealed that C1 binds to small, homogeneous interfaces at the periphery of the antibody platforms. Here, we have developed a novel strategy for complement activation using macrocyclic peptides designed to mimic the interface between antibodies and the C1 complex. In vitro selection utilizing the RaPID system identified a cyclic peptide (cL3) that binds to the C1 complex via the globular head domains of C1q. Notably, when immobilized on surfaces, cL3 effectively recruits C1 from human serum, activates C1s proteases, and induces lysis of cell-mimetic lipid membranes. This represents the first instance of a peptide capable of activating complement by binding C1 when immobilized. Further characterization and synthesis of deletion mutants revealed a critical cycle size of cL3 essential for C1 binding and efficient complement activation. Importantly, cL3 also demonstrated the ability to inhibit complement-mediated lysis without affecting C1 binding, highlighting its potential as a therapeutic modality to prevent complement-dependent cytotoxicity whilst promoting cellular phagocytosis and cell clearance. In summary, this study introduces the concept of “Peptactins” – peptide-based activators of complement – and underscores the potential of macrocyclic peptides for complement modulation, offering potential advantages over traditional biologicals in terms of size, production, and administration.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 787-799"},"PeriodicalIF":4.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00081a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141548941","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

Probing the metalloproteome: an 8-mercaptoquinoline motif enriches minichromosome maintenance complex components as significant metalloprotein targets in live cells† 探究金属蛋白组：8-巯基喹啉基团将迷你染色体维护复合体成分富集为活细胞中重要的金属蛋白靶标

IF 4.2

RSC Chemical Biology Pub Date : 2024-06-25 DOI: 10.1039/D4CB00053F

Sean M. McKenna, Bogdan I. Florea, Daniela M. Zisterer, Sander I. van Kasteren and Joanna F. McGouran

{"title":"Probing the metalloproteome: an 8-mercaptoquinoline motif enriches minichromosome maintenance complex components as significant metalloprotein targets in live cells†","authors":"Sean M. McKenna, Bogdan I. Florea, Daniela M. Zisterer, Sander I. van Kasteren and Joanna F. McGouran","doi":"10.1039/D4CB00053F","DOIUrl":"10.1039/D4CB00053F","url":null,"abstract":"Affinity-based probes are valuable tools for detecting binding interactions between small molecules and proteins in complex biological environments. Metalloproteins are a class of therapeutically significant biomolecules which bind metal ions as part of key structural or catalytic domains and are compelling targets for study. However, there is currently a limited range of chemical tools suitable for profiling the metalloproteome. Here, we describe the preparation and application of a novel, photoactivatable affinity-based probe for detection of a subset of previously challenging to engage metalloproteins. The probe, bearing an 8-mercaptoquinoline metal chelator, was anticipated to engage several zinc metalloproteins, including the 26S-proteasome subunit Rpn11. Upon translation of the labelling experiment to mammalian cell lysate and live cell experiments, proteomic analysis revealed that several metalloproteins were competitively enriched. The diazirine probe SMK-24 was found to effectively enrich multiple components of the minichromosome maintenance complex, a zinc metalloprotein assembly with helicase activity essential to DNA replication. Cell cycle analysis experiments revealed that HEK293 cells treated with SMK-24 experienced stalling in G0/G1 phase, consistent with inactivation of the DNA helicase complex. This work represents an important contribution to the library of cell-permeable chemical tools for studying a collection of metalloproteins for which no previous probe existed.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 776-786"},"PeriodicalIF":4.2,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00053f?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141552589","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

Cluster effect through the oligomerisation of bioactive disaccharide AMOR on pollen tube capacitation in Torenia fournieri† 通过生物活性双糖 AMOR 的低聚作用，对 Torenia fournieri 的花粉管获能产生簇集效应

IF 4.2

RSC Chemical Biology Pub Date : 2024-06-19 DOI: 10.1039/D4CB00032C

Akane G. Mizukami, Shuhei Kusano, Kumi Matsuura-Tokita, Shinya Hagihara and Tetsuya Higashiyama

引用次数: 0

Toward once-monthly insulin therapy via synergy in two pharmacokinetic protractors: Fc-conjugation and fatty acid acylation† 通过两种药代动力学原器的协同作用，实现每月一次的胰岛素治疗：Fc 结合和脂肪酸酰化

IF 4.2

RSC Chemical Biology Pub Date : 2024-06-18 DOI: 10.1039/D4CB00078A

Alexander N. Zaykov, Vasily M. Gelfanov, Tina M. Tagmose, Damien Demozay, Valentina Manfè, Rebecca Rohlfs, Marita Rivir, Diego Perez-Tilve, Brian Finan and Richard D. DiMarchi

引用次数: 0

DNA encoded peptide library for SARS-CoV-2 3CL protease covalent inhibitor discovery and profiling† 用于发现和分析 SARS-CoV-2 3CL 蛋白酶共价抑制剂的 DNA 编码多肽库†。

IF 4.2

RSC Chemical Biology Pub Date : 2024-06-11 DOI: 10.1039/D4CB00097H

Yuyu Xing, Huiya Zhang, Yanhui Wang, Zhaoyun Zong, Matthew Bogyo and Shiyu Chen

{"title":"DNA encoded peptide library for SARS-CoV-2 3CL protease covalent inhibitor discovery and profiling†","authors":"Yuyu Xing, Huiya Zhang, Yanhui Wang, Zhaoyun Zong, Matthew Bogyo and Shiyu Chen","doi":"10.1039/D4CB00097H","DOIUrl":"https://doi.org/10.1039/D4CB00097H","url":null,"abstract":"Covalent protease inhibitors serve as valuable tools for modulating protease activity and are essential for investigating the functions of protease targets. These inhibitors typically consist of a recognition motif and a covalently reactive electrophile. Substrate peptides, featuring residues capable of fitting into the substrate pockets of proteases, undergo chemical modification at the carbonyl carbon of the P1 residue with an electrophile and have been widely applied in the development of covalent inhibitors. In this study, we utilized a DNA-encoded peptide library to replicate peptide binder sequences and introduced a vinyl sulfone warhead at the C-termini to construct the DNA-encoded peptide covalent inhibitor library (DEPCIL) for targeting cysteine proteases. Screening results toward 3CL protease demonstrated the efficacy of this library, not only in identifying protease inhibitors, but also in discovering amino acids that can conform to aligned protease pockets. The identified peptide sequences provide valuable insight into the amino acid preferences within substrate binding pockets, and our novel technology is indicative of the potential for similar strategies to discover covalent inhibitors and profile binding preferences of other proteases.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 7","pages":" 691-702"},"PeriodicalIF":4.2,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00097h?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500470","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

Natural triterpenoid-aided identification of the druggable interface of HMGB1 occupied by TLR4† 天然三萜类化合物辅助鉴定 TLR4 占用的 HMGB1 药物界面

IF 4.2

RSC Chemical Biology Pub Date : 2024-06-07 DOI: 10.1039/D4CB00062E

Pingping Shen, Xuewa Jiang, Yi Kuang, Weiwei Wang, Richa Raj, Wei Wang, Yuyuan Zhu, Xiaochun Zhang, Boyang Yu and Jian Zhang

{"title":"Natural triterpenoid-aided identification of the druggable interface of HMGB1 occupied by TLR4†","authors":"Pingping Shen, Xuewa Jiang, Yi Kuang, Weiwei Wang, Richa Raj, Wei Wang, Yuyuan Zhu, Xiaochun Zhang, Boyang Yu and Jian Zhang","doi":"10.1039/D4CB00062E","DOIUrl":"10.1039/D4CB00062E","url":null,"abstract":"HMGB1 interacts with TLR4 to activate the inflammatory cascade response, contributing to the pathogenesis of endogenous tissue damage and infection. The immense importance of HMGB1–TLR4 interaction in the immune system has made its binding interface an area of significant interest. To map the binding interface of HMGB1 occupied by TLR4, triterpenoids that disrupt the HMGB1–TLR4 interaction and interfere with HMGB1-induced inflammation were developed. Using the unique triterpenoid PT-22 as a probe along with photoaffinity labeling and site-directed mutagenesis, we found that the binding interface of HMGB1 was responsible for the recognition of TLR4 located on the “L” shaped B-box with K114 as a crucial hot-spot residue. Amazingly, this highly conserved interaction surface overlapped with the antigen-recognition epitope of an anti-HMGB1 antibody. Our findings propose a novel strategy for better understanding the druggable interface of HMGB1 that interacts with TLR4 and provide insights for the rational design of HMGB1–TLR4 PPI inhibitors to fine tune immune responses.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 751-762"},"PeriodicalIF":4.2,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00062e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141552590","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

Affinity enhancement of polo-like kinase 1 polo box domain-binding ligands by a bivalent approach using a covalent kinase-binding component† 通过使用共价激酶结合成分的二价方法增强多聚激酶1多聚盒结构域结合配体的亲和力

IF 4.2

RSC Chemical Biology Pub Date : 2024-06-04 DOI: 10.1039/D4CB00031E

Kohei Tsuji, Hirokazu Tamamura and Terrence R. Burke

{"title":"Affinity enhancement of polo-like kinase 1 polo box domain-binding ligands by a bivalent approach using a covalent kinase-binding component†","authors":"Kohei Tsuji, Hirokazu Tamamura and Terrence R. Burke","doi":"10.1039/D4CB00031E","DOIUrl":"10.1039/D4CB00031E","url":null,"abstract":"The polo-like kinase 1 (Plk1) is an important cell cycle regulator that is recognized as a target molecule for development of anti-cancer agents. Plk1 consists of a catalytic kinase domain (KD) and a polo-box domain (PBD), which engages in protein–protein interactions (PPIs) essential to proper Plk1 function. Recently, we developed extremely high-affinity PBD-binding inhibitors based on a bivalent approach using the Plk1 KD-binding inhibitor, BI2536, and a PBD-binding peptide. Certain of the resulting bivalent constructs exhibited more than 100-fold Plk1 affinity enhancement relative to the best monovalent PBD-binding ligands. Herein, we report an extensive investigation of bivalent ligands that utilize the non-selective kinase inhibitor Wortmannin as a Plk1 KD-binding component. We found that bivalent ligands incorporating Wortmannin demonstrated affinity enhancements that could be similar to what we had obtained with BI2536 and that they could tightly bind to the protein. This suggests that these tight binding ligands might be useful for structural analysis of full-length Plk1.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 721-728"},"PeriodicalIF":4.2,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00031e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141548944","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

Seleno-relaxin analogues: effect of internal and external diselenide bonds on the foldability and a fibrosis-related factor of endometriotic stromal cells† 硒-松弛素类似物：内外二硒化键对子宫内膜异位症基质细胞可折叠性和一种纤维化相关因子的影响

IF 4.2

RSC Chemical Biology Pub Date : 2024-05-31 DOI: 10.1039/D4CB00095A

Yuri Satoh, Yosuke Ono, Rikana Takahashi, Hidekazu Katayama, Michio Iwaoka, Osamu Yoshino and Kenta Arai

{"title":"Seleno-relaxin analogues: effect of internal and external diselenide bonds on the foldability and a fibrosis-related factor of endometriotic stromal cells†","authors":"Yuri Satoh, Yosuke Ono, Rikana Takahashi, Hidekazu Katayama, Michio Iwaoka, Osamu Yoshino and Kenta Arai","doi":"10.1039/D4CB00095A","DOIUrl":"10.1039/D4CB00095A","url":null,"abstract":"Human relaxin-2 (H2 relaxin) is a peptide hormone of about 6 kDa, first identified as a reproductive hormone involved in vasoregulation during pregnancy. It has recently attracted strong interest because of its diverse functions, including anti-inflammatory, anti-fibrotic, and vasodilatory, and has been suggested as a potential peptide-based drug candidate for a variety of diseases. Mature H2 relaxin is constituted by the A- and B-chains stabilized by two interchain disulfide (SS) bridges and one intrachain SS linkage. In this study, seleno-relaxins, SeRlx-α and SeRlx-β, which are [C11UA,C11UB] and [C10UA,C15UA] variants of H2 relaxin, respectively, were synthesized via a one-pot oxidative chain assembly (folding) from the component A- and B-chains. The substitution of SS bonds in a protein with their analogue, diselenide (SeSe) bonds, has been shown to alter the physical, chemical, and physiological properties of the protein. The surface SeSe bond (U11A–U11B) enhanced the yield of chain assembly while the internal SeSe bond (U10A–U15A) improved the reaction rate of the folding, indicating that these bridges play a major role in controlling the thermodynamics and kinetics, respectively, of the folding mechanism. Furthermore, SeRlx-α and SeRlx-β effectively reduced the expression of a tissue fibrosis-related factor in human endometriotic stromal cells. Thus, the findings of this study indicate that the S-to-Se substitution strategy not only enhances the foldability of relaxin, but also provides new guidance for the development of novel relaxin formulations for endometriosis treatment.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 729-737"},"PeriodicalIF":4.2,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00095a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198171","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

Site-directed allostery perturbation to probe the negative regulation of hypoxia inducible factor-1α† 通过定点异源扰动探究缺氧诱导因子-1α的负调控作用

IF 4.2

RSC Chemical Biology Pub Date : 2024-05-30 DOI: 10.1039/D4CB00066H

Vencel L. Petrovicz, István Pasztuhov, Tamás A. Martinek and Zsófia Hegedüs

{"title":"Site-directed allostery perturbation to probe the negative regulation of hypoxia inducible factor-1α†","authors":"Vencel L. Petrovicz, István Pasztuhov, Tamás A. Martinek and Zsófia Hegedüs","doi":"10.1039/D4CB00066H","DOIUrl":"10.1039/D4CB00066H","url":null,"abstract":"The interaction between the intrinsically disordered transcription factor HIF-1α and the coactivator proteins p300/CBP is essential in the fast response to low oxygenation. The negative feedback regulator, CITED2, switches off the hypoxic response through a very efficient irreversible mechanism. The negative cooperativity with HIF-1α relies on the formation of a ternary intermediate that leads to allosteric structural changes in p300/CBP, in which the cooperative folding/binding of the CITED2 sequence motifs plays a key role. Understanding the contribution of a binding motif to the structural changes in relation to competition efficiency provides invaluable insights into the molecular mechanism. Our strategy is to site-directedly perturb the p300–CITED2 complex's structure without significantly affecting binding thermodynamics. In this way, the contribution of a sequence motif to the negative cooperativity with HIF-1α would mainly depend on the induced structural changes, and to a lesser extent on binding affinity. Using biophysical assays and NMR measurements, we show here that the interplay between the N-terminal tail and the rest of the binding motifs of CITED2 is crucial for the unidirectional displacement of HIF-1α. We introduce an advantageous approach for evaluating the roles of the different sequence parts with the help of motif-by-motif backbone perturbations.","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 8","pages":" 711-720"},"PeriodicalIF":4.2,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/cb/d4cb00066h?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141191064","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