Herbal medicines (HMs) are gaining increasing popularity and recognition worldwide due to their eco-friendliness and efficacy. With their multi-compounds, multi-targets, and multi-pathways characteristics, HMs have been used in treatment of various diseases. However, the clinical applications of preparations containing HMs have been limited due to their inherent physicochemical properties, including low water solubility, poor stability, and unsatisfactory bioavailability of bioactive compounds. Supramolecular macrocyclic hosts, like cyclodextrins, calixarenes, cucurbiturils, and pillararenes, are important objects of researches in supramolecular chemistry. These hosts have been utilized to encapsulate the ingredients, improve the solubility of poorly water-soluble components, enhance the stability of the tested compounds, increase the bioavailability of bioactive compounds, and ensure the safety of HMs. Herein, we provide a brief introduction to the theories of supramolecular chemistry and summarize the extensive applications of supramolecular macrocyclic hosts in the field of HMs. These applications encompass the screening of bioactive compounds in HMs and the enhancement of druggability for HMs. We hope this review can provide a strategy for dealing with the challenges of HMs, thereby enabling their better applications and development.
草药(HMs)因其生态友好性和疗效日益受到全世界的欢迎和认可。HMs 具有多化合物、多靶点和多途径的特点,已被用于治疗各种疾病。然而,由于其固有的理化特性,包括水溶性低、稳定性差、生物活性化合物的生物利用度不理想等,含有 HMs 的制剂的临床应用一直受到限制。超分子大环宿主,如环糊精、钙烯、葫芦烯和支柱烯,是超分子化学研究的重要对象。这些宿主被用来封装成分,改善水溶性差的成分的溶解性,提高被测化合物的稳定性,增加生物活性化合物的生物利用度,并确保 HMs 的安全性。在此,我们简要介绍了超分子化学理论,并总结了超分子大环宿主在 HMs 领域的广泛应用。这些应用包括在 HMs 中筛选生物活性化合物和提高 HMs 的可药性。我们希望这篇综述能为应对 HMs 的挑战提供策略,从而使 HMs 得到更好的应用和发展。
{"title":"Practical Applications of Supramolecular Macrocyclic Hosts in the Field of Herbal Medicines","authors":"Huijuan Yu, Kejing Niu, Yuting Zhao, Yuefei Wang","doi":"10.1002/ijch.202300179","DOIUrl":"10.1002/ijch.202300179","url":null,"abstract":"<p>Herbal medicines (HMs) are gaining increasing popularity and recognition worldwide due to their eco-friendliness and efficacy. With their multi-compounds, multi-targets, and multi-pathways characteristics, HMs have been used in treatment of various diseases. However, the clinical applications of preparations containing HMs have been limited due to their inherent physicochemical properties, including low water solubility, poor stability, and unsatisfactory bioavailability of bioactive compounds. Supramolecular macrocyclic hosts, like cyclodextrins, calixarenes, cucurbiturils, and pillararenes, are important objects of researches in supramolecular chemistry. These hosts have been utilized to encapsulate the ingredients, improve the solubility of poorly water-soluble components, enhance the stability of the tested compounds, increase the bioavailability of bioactive compounds, and ensure the safety of HMs. Herein, we provide a brief introduction to the theories of supramolecular chemistry and summarize the extensive applications of supramolecular macrocyclic hosts in the field of HMs. These applications encompass the screening of bioactive compounds in HMs and the enhancement of druggability for HMs. We hope this review can provide a strategy for dealing with the challenges of HMs, thereby enabling their better applications and development.</p>","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141343353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antonius J P Hopstaken, Enno Große Wichtrup, S. Jongkees
In ribosomal synthesis of peptides and proteins, genetic information is translated into an amino acid polymer according to the genetic code, which describes the translational command encoded by each codon. However, parts of the genetic code can be adjusted to customize translations. One option is to remove decoding for a specific codon, resulting in a vacant codon. Such vacant codons can be used to stall the ribosome for mechanistic studies and display techniques. Alternatively, the liberated codon can be assigned to encode for incorporation of a noncanonical building block for expansion of the genetic code. In this review we provide an overview of the methods currently available for vacating codons in prokaryotic translation (agnostic of how these are later applied), targeting factors such as amino‐acyl tRNA synthetases, tRNA, release factors, and the initiation machinery. Moreover, we assess applicability and compatibility of the currently available techniques and discuss which have the potential to develop into even more powerful approaches in the future.
{"title":"The Great Codon Escape: Vacating Codons for Genetic Code Expansion and Ribosome Stalling","authors":"Antonius J P Hopstaken, Enno Große Wichtrup, S. Jongkees","doi":"10.1002/ijch.202400012","DOIUrl":"https://doi.org/10.1002/ijch.202400012","url":null,"abstract":"In ribosomal synthesis of peptides and proteins, genetic information is translated into an amino acid polymer according to the genetic code, which describes the translational command encoded by each codon. However, parts of the genetic code can be adjusted to customize translations. One option is to remove decoding for a specific codon, resulting in a vacant codon. Such vacant codons can be used to stall the ribosome for mechanistic studies and display techniques. Alternatively, the liberated codon can be assigned to encode for incorporation of a noncanonical building block for expansion of the genetic code. In this review we provide an overview of the methods currently available for vacating codons in prokaryotic translation (agnostic of how these are later applied), targeting factors such as amino‐acyl tRNA synthetases, tRNA, release factors, and the initiation machinery. Moreover, we assess applicability and compatibility of the currently available techniques and discuss which have the potential to develop into even more powerful approaches in the future.","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141352039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A promising, but not yet practiced, approach to the treatment of neurotoxic organophosphate poisoning is the administration of a scavenger that rapidly deactivates the nerve agent before it can exert its toxic effects. The detoxification rates required for successful use of this therapy can currently only be achieved with enzymes, but synthetic scavengers, whose mode of action is based on key concepts of supramolecular chemistry, are an attractive alternative. Considerable progress has recently been made in the development of such scavengers, and compounds from several receptor classes are now available that not only bind nerve agents but also degrade them at promising rates. This review provides an overview of the field and highlights recent developments.
{"title":"Supramolecular Approaches to the Detoxification of Nerve Agents","authors":"Prof. Dr. Stefan Kubik","doi":"10.1002/ijch.202400019","DOIUrl":"10.1002/ijch.202400019","url":null,"abstract":"<p>A promising, but not yet practiced, approach to the treatment of neurotoxic organophosphate poisoning is the administration of a scavenger that rapidly deactivates the nerve agent before it can exert its toxic effects. The detoxification rates required for successful use of this therapy can currently only be achieved with enzymes, but synthetic scavengers, whose mode of action is based on key concepts of supramolecular chemistry, are an attractive alternative. Considerable progress has recently been made in the development of such scavengers, and compounds from several receptor classes are now available that not only bind nerve agents but also degrade them at promising rates. This review provides an overview of the field and highlights recent developments.</p>","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijch.202400019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141357892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The intricate network of cell functions relies on gene expression programs, where the whole RNA life cycle from DNA to protein is subjected to extensive transcriptional and post-transcriptional gene regulation events. Established bulk RNA sequencing methods provide an averaged, transcriptome-wide quantification of the RNA life cycle, including transcription, processing, translation, transport, and degradation through RNA-protein interactions. Furthermore, numerous studies using bulk epitranscriptomic profiling unveiled that dynamic RNA modifications (e. g., N6-Methyladenosine), add another layer of gene regulations. However, many regulatory events are cell-type specific, subcellularly localized, and subjected to cell-cell communications within the native tissue environment. Thanks to the advances in single-cell sequencing, spatial sequencing, and highly multiplexed imaging methods, we can routinely measure single-cell and spatial transcriptomics. Yet more comprehensive methods to profile every step of the RNA life cycle with single-cell and spatial information are still lacking. In this review, we will summarize and compare early explorations in developing state-of-the-art methods for spatially and single-cell resolved mapping of RNA kinetics, translation, RNA-protein interactions, and epitranscriptomics. It is promising that these new techniques will greatly facilitate our understanding of the RNA-centered regulation landscapes in different cell types and how the post-transcriptional regulations are interconnected within cellular and tissue architecture.
{"title":"Spatially and Single-Cell Resolved Profiling of RNA Life Cycle and Epitranscriptomics","authors":"Qiyang Zhou, Jianting Guo, Xiao Wang","doi":"10.1002/ijch.202400028","DOIUrl":"10.1002/ijch.202400028","url":null,"abstract":"<p>The intricate network of cell functions relies on gene expression programs, where the whole RNA life cycle from DNA to protein is subjected to extensive transcriptional and post-transcriptional gene regulation events. Established bulk RNA sequencing methods provide an averaged, transcriptome-wide quantification of the RNA life cycle, including transcription, processing, translation, transport, and degradation through RNA-protein interactions. Furthermore, numerous studies using bulk epitranscriptomic profiling unveiled that dynamic RNA modifications (e. g., <i>N</i><sup>6</sup>-Methyladenosine), add another layer of gene regulations. However, many regulatory events are cell-type specific, subcellularly localized, and subjected to cell-cell communications within the native tissue environment. Thanks to the advances in single-cell sequencing, spatial sequencing, and highly multiplexed imaging methods, we can routinely measure single-cell and spatial transcriptomics. Yet more comprehensive methods to profile every step of the RNA life cycle with single-cell and spatial information are still lacking. In this review, we will summarize and compare early explorations in developing state-of-the-art methods for spatially and single-cell resolved mapping of RNA kinetics, translation, RNA-protein interactions, and epitranscriptomics. It is promising that these new techniques will greatly facilitate our understanding of the RNA-centered regulation landscapes in different cell types and how the post-transcriptional regulations are interconnected within cellular and tissue architecture.</p>","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijch.202400028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141270198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular DNA and RNA are decorated with diverse chemical modifications, which add new layers to gene regulation and play crucial roles across development and disease progression. Interest in understanding the functions of DNA and RNA modifications, as well as the related molecular mechanisms, has been growing, driving progress in developing chemical and biochemical tools to detect specific modifications. New technologies are important not only for uncovering biological functions, but also for driving conceptual revolutions. In this review, we highlighted our recent advances in developing new chemical tools to detect DNA and RNA modifications in a direct, quantitative, and base-resolution manner. These includes a novel borane reduction chemistry for DNA methylation sequencing; new cytosine modificaiton oxdation chemistry for enhanced DNA hydroxymethylation sequencing; and a novel bromoacrylamide cyclization chemistry for RNA pseudouridylation sequencing. We present a mechanistic overview of these tools and their applications in epigenetic and epitranscriptomic research.
细胞 DNA 和 RNA 上有多种多样的化学修饰,它们为基因调控增添了新的层次,并在发育和疾病进程中发挥着至关重要的作用。人们对了解 DNA 和 RNA 修饰的功能以及相关分子机制的兴趣与日俱增,推动了检测特定修饰的化学和生化工具的开发进展。新技术不仅对揭示生物功能很重要,而且对推动概念革命也很重要。在这篇综述中,我们重点介绍了最近在开发新的化学工具以直接、定量和碱基分辨的方式检测 DNA 和 RNA 修饰方面取得的进展。其中包括用于 DNA 甲基化测序的新型硼烷还原化学;用于增强 DNA 羟甲基化测序的新型胞嘧啶修饰氧化化学;以及用于 RNA 伪尿嘧啶化测序的新型溴丙烯酰胺环化化学。我们从机理上概述了这些工具及其在表观遗传学和表观转录组学研究中的应用。
{"title":"Direct, Quantitative, and Base-Resolution Sequencing of DNA and RNA Modifications","authors":"Haiqi Xu, Chun-Xiao Song","doi":"10.1002/ijch.202400007","DOIUrl":"10.1002/ijch.202400007","url":null,"abstract":"<p>Cellular DNA and RNA are decorated with diverse chemical modifications, which add new layers to gene regulation and play crucial roles across development and disease progression. Interest in understanding the functions of DNA and RNA modifications, as well as the related molecular mechanisms, has been growing, driving progress in developing chemical and biochemical tools to detect specific modifications. New technologies are important not only for uncovering biological functions, but also for driving conceptual revolutions. In this review, we highlighted our recent advances in developing new chemical tools to detect DNA and RNA modifications in a direct, quantitative, and base-resolution manner. These includes a novel borane reduction chemistry for DNA methylation sequencing; new cytosine modificaiton oxdation chemistry for enhanced DNA hydroxymethylation sequencing; and a novel bromoacrylamide cyclization chemistry for RNA pseudouridylation sequencing. We present a mechanistic overview of these tools and their applications in epigenetic and epitranscriptomic research.</p>","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijch.202400007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141197612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Goonho Park, Angela Galdamez, Keon‐Hyoung Song, Masako Le, Kyle Kim, Jonathan H. Lin
EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss‐of‐function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of common PERK polymorphisms linked to tauopathies. Using SWISS‐MODEL, we identified structural perturbations in the ER stress‐sensing luminal domain dimers/oligomers of tauopathy‐associated PERK variants, Haplotypes A and B, in combination with another tauopathy‐linked R240H mutation. Recombinant expression of disease‐associated variants in vitro revealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non‐disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.
EIF2AK3 又称 PERK,在细胞蛋白稳态中发挥着关键作用,协调着折叠蛋白反应(UPR)和综合应激反应(ISR)途径。除了在细胞内应力调控中的核心地位外,人类 GWAS 还发现 EIF2AK3 是 tau 病(由 tau 蛋白异常积累引起的神经退行性疾病)的风险因素。在这些基因组指标的指导下,我们的研究对人类 PERK 变异进行了系统分析,重点关注那些与牛头蛋白病有潜在联系的变异。我们参考 gnomAD、Ensembl 和 NCBI 数据库,收集了与 Wolcott Rallison 综合征(WRS)、tauopathies 和生物信息学预测的功能缺失相关的人类 PERK 变异的综合数据集。我们发现,与陶陶病相关的常见 PERK 多态性的发生率存在广泛的种族/民族差异。利用 SWISS-MODEL,我们确定了与牛磺酸脑病相关的 PERK 变体 Haplotypes A 和 B 与另一种与牛磺酸脑病相关的 R240H 突变相结合的 ER 应激传感腔域二聚体/高聚体的结构扰动。在体外重组表达疾病相关变体时发现,与占主导地位的非疾病变体相比,PERK 信号转导动力学对 ER 压力的响应发生了改变。总之,我们的数据进一步证实,在牛磺酸脑病基因研究中发现的人类 PERK 变异对 PERK 的结构、功能和下游信号转导产生了负面影响,而且在不同种族和民族群体中的发生率存在显著差异。
{"title":"Ethnic Variation and Structure‐Function Analysis of Tauopathy‐Associated PERK Alleles","authors":"Goonho Park, Angela Galdamez, Keon‐Hyoung Song, Masako Le, Kyle Kim, Jonathan H. Lin","doi":"10.1002/ijch.202300173","DOIUrl":"https://doi.org/10.1002/ijch.202300173","url":null,"abstract":"EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss‐of‐function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of common <jats:italic>PERK</jats:italic> polymorphisms linked to tauopathies. Using SWISS‐MODEL, we identified structural perturbations in the ER stress‐sensing luminal domain dimers/oligomers of tauopathy‐associated PERK variants, Haplotypes A and B, in combination with another tauopathy‐linked R240H mutation. Recombinant expression of disease‐associated variants <jats:italic>in vitro</jats:italic> revealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non‐disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141152436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shape-persistent organic cages are an intriguing class of molecular porous materials. Through hierarchical molecular design, size and shape of the intrinsic molecular voids are controlled by dynamic covalent chemistry, while pore structure and topology are governed by noncovalent alignment in the solid state. However, the predictable and reliable crystallization of organic cages is still challenging since long-range superstructures are solely based on weak and rather unidirectional supramolecular interactions. In this tutorial review, we provide a general classification of porous solid-state materials and discuss specific design principles regarding the dynamic covalent reactions, the small-molecule building blocks and solid-state engineering. Furthermore, we introduce the most important analytical techniques for porous materials with a special focus on organic cages.
{"title":"Porous Crystalline Organic Cages Made by Design","authors":"Dr. Svetlana Ivanova, Prof. Dr. Florian Beuerle","doi":"10.1002/ijch.202400025","DOIUrl":"10.1002/ijch.202400025","url":null,"abstract":"<p>Shape-persistent organic cages are an intriguing class of molecular porous materials. Through hierarchical molecular design, size and shape of the intrinsic molecular voids are controlled by dynamic covalent chemistry, while pore structure and topology are governed by noncovalent alignment in the solid state. However, the predictable and reliable crystallization of organic cages is still challenging since long-range superstructures are solely based on weak and rather unidirectional supramolecular interactions. In this tutorial review, we provide a general classification of porous solid-state materials and discuss specific design principles regarding the dynamic covalent reactions, the small-molecule building blocks and solid-state engineering. Furthermore, we introduce the most important analytical techniques for porous materials with a special focus on organic cages.</p>","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijch.202400025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140973743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cytokines play a central role in regulating cell communication and signal transduction, since they influence processes such as immunity, hematopoiesis, inflammatory disease, cancer, neurological disorders, and tissue healing. Notably, certain cytokines have been used clinically as protein therapeutics for conditions such as cancer, autoimmune diseases, and viral infections. Despite their therapeutic potential, cytokines often pose challenges, including side effects, stability constraints, and suboptimal pharmacokinetics. To address these limitations, there is growing interest in using diverse modalities to develop alternative cytokines with enhanced properties and therapeutic benefits. Of these modalities, effective high‐throughput screening of macrocyclic peptides enabled by RNA‐based catalysis has emerged as a promising candidate method for the development of alternative cytokines. Here, we focus on the development of cytokine alternatives using various approaches and explore prospects for their future use as therapeutic agents.
{"title":"Cytokine Mimetics with Various Modalities","authors":"Katsuya Sakai, Hiroki Sato, Kunio Matsumoto","doi":"10.1002/ijch.202300163","DOIUrl":"https://doi.org/10.1002/ijch.202300163","url":null,"abstract":"Cytokines play a central role in regulating cell communication and signal transduction, since they influence processes such as immunity, hematopoiesis, inflammatory disease, cancer, neurological disorders, and tissue healing. Notably, certain cytokines have been used clinically as protein therapeutics for conditions such as cancer, autoimmune diseases, and viral infections. Despite their therapeutic potential, cytokines often pose challenges, including side effects, stability constraints, and suboptimal pharmacokinetics. To address these limitations, there is growing interest in using diverse modalities to develop alternative cytokines with enhanced properties and therapeutic benefits. Of these modalities, effective high‐throughput screening of macrocyclic peptides enabled by RNA‐based catalysis has emerged as a promising candidate method for the development of alternative cytokines. Here, we focus on the development of cytokine alternatives using various approaches and explore prospects for their future use as therapeutic agents.","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140980242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Xie, Meng‐Wei Kan, Simon J. de Veer, Conan Wang, David J. Craik
Cyclotides are ultra‐stable peptides originally discovered in plants based on their medicinal applications. Their natural function is as host defence agents. They are amenable to chemical synthesis for use as scaffolds for drug design applications. Cyclotides comprise ~30 amino acids and in addition to having a head‐to‐tail cyclic backbone, incorporate six conserved cystine residues connected in a cystine knot motif. The cyclic backbone and cystine knot contribute to their exceptional resistance to proteases or thermal denaturation, making them useful scaffolds for drug design applications. The backbone segments, or loops, between the conserved cysteine residues are amenable to combinatorial variation in native cyclotides and have also been used to incorporate selected bioactive peptide epitopes into a range of synthetic cyclotides and cyclotide‐like scaffolds. In the past this was largely done via low throughput structure‐based design approaches, but the discovery of novel cyclotide binders has been greatly enhanced by the use of combinatorial display approaches on cyclotide scaffolds using phage, bacterial, yeast and mRNA technologies, as reviewed herein.
{"title":"Display Technologies for Expanding the Pharmaceutical Applications of Cyclotides","authors":"Jing Xie, Meng‐Wei Kan, Simon J. de Veer, Conan Wang, David J. Craik","doi":"10.1002/ijch.202400010","DOIUrl":"https://doi.org/10.1002/ijch.202400010","url":null,"abstract":"Cyclotides are ultra‐stable peptides originally discovered in plants based on their medicinal applications. Their natural function is as host defence agents. They are amenable to chemical synthesis for use as scaffolds for drug design applications. Cyclotides comprise ~30 amino acids and in addition to having a head‐to‐tail cyclic backbone, incorporate six conserved cystine residues connected in a cystine knot motif. The cyclic backbone and cystine knot contribute to their exceptional resistance to proteases or thermal denaturation, making them useful scaffolds for drug design applications. The backbone segments, or loops, between the conserved cysteine residues are amenable to combinatorial variation in native cyclotides and have also been used to incorporate selected bioactive peptide epitopes into a range of synthetic cyclotides and cyclotide‐like scaffolds. In the past this was largely done via low throughput structure‐based design approaches, but the discovery of novel cyclotide binders has been greatly enhanced by the use of combinatorial display approaches on cyclotide scaffolds using phage, bacterial, yeast and mRNA technologies, as reviewed herein.","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rylan R. Watkins, Arundhati Kavoor, Karin Musier‐Forsyth
Aminoacyl‐tRNA synthetases (aaRSs) maintain translational fidelity by ensuring the formation of correct aminoacyl‐tRNA pairs. Numerous point mutations in human aaRSs have been linked to disease phenotypes. Structural studies of aaRSs from human pathogens encoding unique domains support these enzymes as potential candidates for therapeutics. Studies have shown that the identity of tRNA pools in cells changes between different cell types and under stress conditions. While traditional radioactive aminoacylation analyses can determine the effect of disease‐causing mutations on aaRS function, these assays are not amenable to drug discovery campaigns and do not take into account the variability of the intracellular tRNA pools. Here, we review modern techniques to characterize aaRS activity in vitro and in cells. The cell‐based approaches analyse the aminoacyl‐tRNA pool to observe trends in aaRS activity and fidelity. Taken together, these approaches allow high‐throughput drug screening of aaRS inhibitors and systems‐level analyses of the dynamic tRNA population under a variety of conditions and disease states.
{"title":"Strategies for Detecting Aminoacylation and Aminoacyl‐tRNA Editing In Vitro and In Cells","authors":"Rylan R. Watkins, Arundhati Kavoor, Karin Musier‐Forsyth","doi":"10.1002/ijch.202400009","DOIUrl":"https://doi.org/10.1002/ijch.202400009","url":null,"abstract":"Aminoacyl‐tRNA synthetases (aaRSs) maintain translational fidelity by ensuring the formation of correct aminoacyl‐tRNA pairs. Numerous point mutations in human aaRSs have been linked to disease phenotypes. Structural studies of aaRSs from human pathogens encoding unique domains support these enzymes as potential candidates for therapeutics. Studies have shown that the identity of tRNA pools in cells changes between different cell types and under stress conditions. While traditional radioactive aminoacylation analyses can determine the effect of disease‐causing mutations on aaRS function, these assays are not amenable to drug discovery campaigns and do not take into account the variability of the intracellular tRNA pools. Here, we review modern techniques to characterize aaRS activity <jats:italic>in vitro</jats:italic> and in cells. The cell‐based approaches analyse the aminoacyl‐tRNA pool to observe trends in aaRS activity and fidelity. Taken together, these approaches allow high‐throughput drug screening of aaRS inhibitors and systems‐level analyses of the dynamic tRNA population under a variety of conditions and disease states.","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}