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Oligonucleotide-based PROTACs to Degrade RNA- and DNA-Binding Proteins.
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.167
Céline N Weller, Jonathan Hall
{"title":"Oligonucleotide-based PROTACs to Degrade RNA- and DNA-Binding Proteins.","authors":"Céline N Weller, Jonathan Hall","doi":"10.2533/chimia.2025.167","DOIUrl":"https://doi.org/10.2533/chimia.2025.167","url":null,"abstract":"<p><p>Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that sequester the endogenous protein degradation machinery of cells to induce degradation of targeted proteins. By bringing a target protein and a ubiquitin E3 ligase into close proximity, ubiquitin monomers can be transferred onto surface lysines of the protein, which is subsequently degraded by the proteasome. The functions of RNA- and DNA-binding proteins have been especially hard to modulate with small molecules. However, oligonucleotides that bind RNA- or DNA-binding proteins can be turned into oligonucleotide-based PROTACs to direct ubiquitination and degradation of these proteins. Here we summarize the current state of the field of oligonucleotide-based PROTACs that target RNA- or DNA-binding proteins.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"167-171"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742462","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}
引用次数: 0
Reversible Covalent Reactions of Aldehydes and Salicylaldehydes Using a Lysine-Model Substrate.
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.152
Cécile Delmas, Emine Sager, Chrystele Henry, Ulrich Hassiepen, Philip R Skaanderup, Isabel Kerschgens
{"title":"Reversible Covalent Reactions of Aldehydes and Salicylaldehydes Using a Lysine-Model Substrate.","authors":"Cécile Delmas, Emine Sager, Chrystele Henry, Ulrich Hassiepen, Philip R Skaanderup, Isabel Kerschgens","doi":"10.2533/chimia.2025.152","DOIUrl":"https://doi.org/10.2533/chimia.2025.152","url":null,"abstract":"<p><p>Covalent modification of lysine residues has gained significant attention due to its potential application in drug development and chemical biology. Lysine is an essential amino acid, abundant in proteins, and plays a critical role in many biological processes. In this study, we investigated aldehydes for imine-based chemistries and their reactivity profiles using a lysine-surrogate. By monitoring reactions of various aldehydes and salicylaldehydes over time, we determined dissociation constants (KD) for each warhead, reflecting the binding affinity towards the surrogate substrate. Strikingly, our data revealed remarkable differences in affinity depending on the substitution of the warheads. Additionally, we analyzed the kinetic profile of selected aldehydes and salicylaldehydes, which revealed significant disparity in their reaction kinetics. Aldehydes reacted quickly, reaching equilibrium rapidly, whereas salicylaldehydes exhibited considerably slower reaction times, in some cases requiring several hours to reach equilibrium. These differences emphasize how the nature of the warhead structure influences the kinetics of covalent binding to lysine residues. Overall, our study provides valuable insights into the application of reversible covalency to target lysines with reactive warheads that can further inspire development of innovative chemical modifications for drug discovery and chemical biology.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"152-157"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742476","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}
引用次数: 0
Towards the Rational Design of Monovalent Degraders: Lessons Learnt from Cyclin K Degraders.
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.162
Katie L Thomas, Benjamin R Bellenie, Olivia W Rossanese
{"title":"Towards the Rational Design of Monovalent Degraders: Lessons Learnt from Cyclin K Degraders.","authors":"Katie L Thomas, Benjamin R Bellenie, Olivia W Rossanese","doi":"10.2533/chimia.2025.162","DOIUrl":"https://doi.org/10.2533/chimia.2025.162","url":null,"abstract":"<p><p>Monovalent degraders can enhance pre-existing surface complementarity between a target protein and a ligase to induce target degradation via the proteasome. For the most part, degraders have been discovered serendipitously and structure-activity relationship (SAR) studies have been limited, making it difficult to rationally design new compounds. Here we discuss how work on the SAR of cyclin K degraders demonstrates that a broad range of compounds can stabilise protein-protein interactions to induce degradation and how it lays the foundation for further monovalent degrader discovery.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"162-166"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742478","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}
引用次数: 0
Precision Probing of O-GalNAc Glycosylation Using Bump-and-Hole Engineering.
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.146
Abdul Zafar, Benjamin Schumann
{"title":"Precision Probing of O-GalNAc Glycosylation Using Bump-and-Hole Engineering.","authors":"Abdul Zafar, Benjamin Schumann","doi":"10.2533/chimia.2025.146","DOIUrl":"https://doi.org/10.2533/chimia.2025.146","url":null,"abstract":"<p><p>Glycosylation is a profound influencer of glycoprotein function. Glycans have a critical impact on health and disease, yet the tools to study them have trailed behind proteins and nucleic acids. O-GalNAc glycosylation involves the addition of N-acetylgalactosamine (GalNAc) to protein substrates. Dysregulation of O-GalNAc glycosylation is implicated in many pathologies such as cancer. Studying O-GalNAc glycosylation is complicated by the lack of a consensus sequence for initiation and the complex interdependence between a large family of 20 GalNAc transferases (GalNAc-Ts) in human cells. These issues necessitate precise methods of interrogating enzyme function. Herein, we discuss our own advances into the generation of precision tools to study O-GalNAc glycosylation and other glycosylation types. We discuss the use of bump-and-hole engineering to illuminate the roles of individual GalNAc-Ts. Engineering biosynthetic pathways enables cell line-specific uptake of chemical, editable sugars in co-culture settings. We provide an insight into the state-of-the-art in this field.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"146-151"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742466","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}
引用次数: 0
Editorial. 社论
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.125
Amandine Kolleth, Vlad Pascanu
{"title":"Editorial.","authors":"Amandine Kolleth, Vlad Pascanu","doi":"10.2533/chimia.2025.125","DOIUrl":"https://doi.org/10.2533/chimia.2025.125","url":null,"abstract":"","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"125"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742459","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}
引用次数: 0
Recent Advances in CBP/EP300 Degraders.
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.137
Leonardo Palaferri, Iván Cheng-Sánchez, Cristina Nevado
{"title":"Recent Advances in CBP/EP300 Degraders.","authors":"Leonardo Palaferri, Iván Cheng-Sánchez, Cristina Nevado","doi":"10.2533/chimia.2025.137","DOIUrl":"https://doi.org/10.2533/chimia.2025.137","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy, offering advantage over traditional approaches rooted in small-molecule inhibitors. Among the various modalities in TPD, proteolysis targeting chimeras (PROTACs) and molecular glue degraders (MGDs) have arisen as leading modalities, distinguished by their ability to induce protein degradation via the ubiquitin-proteasome system (UPS). In recent years, extensive research has focused on developing degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300) - two homologous multidomain enzymes critical for enhancer-mediated transcription. This review explores the state of the art in CBP/EP300 degraders, underscoring the significant potential of these synthetic bifunctional compounds as innovative chemical tools and highly promising anticancer agents.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"137-145"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742474","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}
引用次数: 0
Challenges and Opportunities in DNA Encoded Library Screens.
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.158
Basilius Sauter, Pinwen Cai, Koder Dagher, Chiara Disraeli, Athira Kakkolliyil Prakash, Lukas Schneider, Ángel Cores Esperon, Dennis Gillingham
{"title":"Challenges and Opportunities in DNA Encoded Library Screens.","authors":"Basilius Sauter, Pinwen Cai, Koder Dagher, Chiara Disraeli, Athira Kakkolliyil Prakash, Lukas Schneider, Ángel Cores Esperon, Dennis Gillingham","doi":"10.2533/chimia.2025.158","DOIUrl":"https://doi.org/10.2533/chimia.2025.158","url":null,"abstract":"<p><p>In our lab we have been developing techniques that attempt to capture or amplify signals in pooled compound mixtures for several years. DNA encoded libraries (DELs) are the most widely used pooled mixtures in early drug discovery. DELs are massive collections of small molecules, where each individual molecule is covalently linked to a unique DNA strand that can serve as an identification tag by sequencing. The industry standard for selecting DELs is affinity enrichment, which inherently can only search for direct binding. We outline here two of the ways that we are attempting to extend the potential of DEL screens into new areas.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"158-161"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742454","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}
引用次数: 0
Control of Therapeutic Activity through Programmed Assembly.
IF 1.1 4区 化学
Chimia Pub Date : 2025-03-26 DOI: 10.2533/chimia.2025.128
Millicent Dockerill, Nicolas Winssinger
{"title":"Control of Therapeutic Activity through Programmed Assembly.","authors":"Millicent Dockerill, Nicolas Winssinger","doi":"10.2533/chimia.2025.128","DOIUrl":"https://doi.org/10.2533/chimia.2025.128","url":null,"abstract":"<p><p>This review explores the control of therapeutic activity through programmed assembly of supramolecular systems. We examine the use of nucleic acids as scaffolds to create tailored assemblies of ligands, including glycan and peptide-based systems, drug-like small molecules or reagents for proximity-induced reactions. We discuss the principles of cooperativity in multivalent interactions, emphasizing their potential to enhance binding affinity and therapeutic efficacy and the opportunity to control their activity through strand displacement. We highlight seminal studies and illustrative case examples and address the challenges faced in translating these designs into clinical applications. Furthermore, we explore recent advancements that demonstrate successful in vivo applications, particularly in the context of anticoagulation therapies. This review aims to provide insights into the future of responsive therapeutic systems that leverage the programmability of supramolecular assemblies to develop potent and adaptable therapeutics.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 3","pages":"128-136"},"PeriodicalIF":1.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742456","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}
引用次数: 0
High-Performance Data Acquisition for Fourier Transform Mass Spectrometry.
IF 1.1 4区 化学
Chimia Pub Date : 2025-02-26 DOI: 10.2533/chimia.2025.77
Anton N Kozhinov, Konstantin O Nagornov, Yury O Tsybin
{"title":"High-Performance Data Acquisition for Fourier Transform Mass Spectrometry.","authors":"Anton N Kozhinov, Konstantin O Nagornov, Yury O Tsybin","doi":"10.2533/chimia.2025.77","DOIUrl":"https://doi.org/10.2533/chimia.2025.77","url":null,"abstract":"<p><p>High-performance data acquisition and processing (DAQ) systems are characterized by their ability to capture, process, and transmit data with high speed, precision, and efficiency. Among commercial solutions for Fourier transform mass spectrometry (FTMS), the FTMS Boosters developed by Spectroswiss stand out. These systems enhance the capabilities of FTMS platforms, such as Orbitrap and ion cyclotron resonance (ICR) instruments, by improving mass resolution, sensitivity, and data handling. This review highlights the impact of FTMS Boosters across six key applications: mass spectrometry imaging, charge detection mass spectrometry (CDMS) and charge determination analysis (CHARDA), biopharmaceutical analysis, isotope ratio and trace analyses, super-resolution mass spectrometry, and complex mixture analysis. By advancing FTMS capabilities, FTMS Boosters not only elevate performance but also extend the operational lifespan of legacy FTMS systems, offering a sustainable and cost-effective path to improved MS functionality. As FTMS technologies advance with an increasing focus on acquiring and processing big data, FTMS Boosters, and other high-performance DAQ systems are set to become indispensable in addressing the growing demands of data-intensive scientific research and applications.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 1-2","pages":"77-83"},"PeriodicalIF":1.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536886","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}
引用次数: 0
Improving Robustness, Sensitivity and Simplicity of Potentiometric Sensors Through Symmetry and Conceptual Design.
IF 1.1 4区 化学
Chimia Pub Date : 2025-02-26 DOI: 10.2533/chimia.2025.7
Eric Bakker
{"title":"Improving Robustness, Sensitivity and Simplicity of Potentiometric Sensors Through Symmetry and Conceptual Design.","authors":"Eric Bakker","doi":"10.2533/chimia.2025.7","DOIUrl":"https://doi.org/10.2533/chimia.2025.7","url":null,"abstract":"<p><p> It is an enormous challenge to bring chemical sensing concepts from a controlled laboratory setting into the field while maintaining accuracy. In an environment of uncontrolled, fluctuating temperatures and a lack of repeated calibration, sensor reliability can rapidly deteriorate the accuracy. Today, many sensing concepts are explored for home use or as wearable sensors, and it is paramount to understand and optimize the chemistry for reliable measurements to become possible. This review focuses on the well-established class of potentiometric sensors, mostly known for the measurement of pH, with a range of electrolytes, and how conceptual advances can be used to make them as robust and sensitive as possible. While drawing from recent work of the group at the University of Geneva, the importance of symmetry is stressed to minimize the influence of temperature. The development of self-powered sensing systems that no longer require a battery is explained. This is then connected to protocols in which the sensitivity of these sensors can be reliably improved beyond that dictated by the Nernst equation.</p>","PeriodicalId":9957,"journal":{"name":"Chimia","volume":"79 1-2","pages":"7-11"},"PeriodicalIF":1.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536888","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}
引用次数: 0
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