ACS Chemical Biology最新文献

{"title":"The Emergence of Oligonucleotide Building Blocks in the Multispecific Proximity-Inducing Drug Toolbox of Destruction.","authors":"Kevin Xiao Tong Zhou, Katherine E Bujold","doi":"10.1021/acschembio.4c00311","DOIUrl":"10.1021/acschembio.4c00311","url":null,"abstract":"<p><p>Oligonucleotides are a rapidly emerging class of therapeutics. Their most well-known examples are informational drugs that modify gene expression by binding mRNA. Despite inducing proximity between biological machinery and mRNA when applied to modulating gene expression, oligonucleotides are not typically labeled as \"proximity-inducing\" in literature. Yet, they have recently been explored as building blocks for multispecific proximity-inducing drugs (MPIDs). MPIDs are unique because they can direct endogenous biological machinery to destroy targeted molecules and cells, in contrast to traditional drugs that inhibit only their functions. The unique mechanism of action of MPIDs has enabled the targeting of previously \"undruggable\" molecular entities that cannot be effectively inhibited. However, the development of MPIDs must ensure that these molecules will selectively direct a potent, destruction-based mechanism of action toward intended targets over healthy tissues to avoid causing life-threatening toxicities. Oligonucleotides have emerged as promising building blocks for the design of MPIDs because they are sequence-controlled molecules that can be rationally designed to program multispecific binding interactions. In this Review, we examine the emergence of oligonucleotide-containing MPIDs in the proximity induction space, which has been dominated by antibody and small molecule MPID modalities. Moreover, examples of oligonucleotides developed as MPID candidates in immunotherapy and protein degradation are discussed to demonstrate the utility of oligonucleotides in expanding the scope and selectivity of the MPID toolbox. Finally, we discuss the utility of programming \"AND\" gates into oligonucleotide scaffolds to encode conditional responses that have the potential to be incorporated into MPIDs, which can further enhance their selectivity, thus increasing the scope of this drug category.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"3-18"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Quinazoline Derivatives Inhibit Splicing of Fungal Group II Introns.","authors":"Olga Fedorova, Michelle Luo, G Erik Jagdmann, Michael C Van Zandt, Luke Sisto, Anna Marie Pyle","doi":"10.1021/acschembio.4c00631","DOIUrl":"https://doi.org/10.1021/acschembio.4c00631","url":null,"abstract":"<p><p>We report the discovery of small molecules that target the RNA tertiary structure of self-splicing group II introns and display potent antifungal activity against yeasts, including the major public health threat <i>Candida parapsilosis</i>. High-throughput screening efforts against a yeast group II intron resulted in an inhibitor class which was then synthetically optimized for enhanced inhibitory activity and antifungal efficacy. The most highly refined compounds in this series display strong, gene-specific antifungal activity against <i>C. parapsilosis</i>. This work demonstrates the utility of combining advanced RNA screening methodologies with medicinal chemistry pipelines to identify high-affinity ligands targeting RNA tertiary structures with important roles in human health and disease.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Key Amino Acids in the A Domains of Polymyxin Synthetase Responsible for 2,4-Diaminobutyric Acid Adenylation in <i>Paenibacillus polymyxa</i> NBRC3020 Strain.","authors":"Mai Nemoto, Wataru Ando, Taichi Mano, Minjae Lee, Satoshi Yuzawa, Toshihisa Mizuno","doi":"10.1021/acschembio.4c00553","DOIUrl":"https://doi.org/10.1021/acschembio.4c00553","url":null,"abstract":"<p><p>Developing novel nonribosomal peptides (NRPs) requires a comprehensive understanding of the enzymes involved in their biosynthesis, particularly the substrate amino acid recognition mechanisms in the adenylation (A) domain. This study focused on the A domain responsible for adenylating l-2,4-diaminobutyric acid (l-Dab) within the synthetase of polymyxin, an NRP produced by <i>Paenibacillus polymyxa</i> NBRC3020. To date, investigations into recombinant proteins that selectively adenylate l-Dab─exploring substrate specificity and enzymatic activity parameters─have been limited to reports on A domains found in enzymes synthesizing l-Dab homopolymers (pldA from <i>S. celluloflavus</i> USE31 and pddA from <i>S. hindustanus</i> NBRC15115), which remain exceedingly rare. The polymyxin synthetase in NBRC3020 contains five A domains specific to l-Dab, distributed across five distinct modules (modules 1, 3, 4, 5, 8, and 9). In this study, we successfully obtained soluble A domain proteins from modules 1, 5, 8, and 9 by preparing module-specific recombinant proteins. These proteins were expressed in <i>E. coli</i> BAP-1, purified via Ni-affinity chromatography, and demonstrated high specificity for l-Dab. Through sequence homology analysis, three-dimensional structural modeling, docking simulations to estimate substrate-binding sites, and functional validation using alanine mutants, we identified Glu281 and Asp344 as critical residues for recognizing the side chain amino group of l-Dab, and Asp238 as essential for recognizing its main chain amino group in the A domain. Notably, these key residues were conserved not only across the A domains in modules 1, 5, 8, and 9 of <i>P. polymyxa</i> NBRC3020 but also in those of the <i>P. polymyxa</i> PKB1 strain, as confirmed by sequence homology analysis. Interestingly, in pldA and pddA, the key residues involved in recognizing the side-chain amino group of l-Dab, which are conserved among polymyxin synthetases of NBRC3020 and PKB1 strain, were not observed. This suggests a potentially different mechanism for l-Dab recognition.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PEGylated ATP-Independent Luciferins for Noninvasive High-Sensitivity High-Speed Bioluminescence Imaging.","authors":"Xiaodong Tian, Yiyu Zhang, Hui-Wang Ai","doi":"10.1021/acschembio.4c00601","DOIUrl":"10.1021/acschembio.4c00601","url":null,"abstract":"<p><p>Bioluminescence imaging (BLI) is a powerful, noninvasive imaging method for animal studies. NanoLuc luciferase and its derivatives are attractive bioluminescent reporters recognized for their efficient photon production and ATP independence. However, utilizing them for animal imaging poses notable challenges. Low substrate solubility has been a prominent problem, limiting <i>in vivo</i> brightness, while the susceptibility of luciferins to auto-oxidation by molecular oxygen in air increases handling complexity and poses an obstacle to obtaining consistent results. To address these issues, we developed a range of caged PEGylated luciferins with increased auto-oxidation resistance and water solubility of up to 25 mM, resulting in substantial <i>in vivo</i> bioluminescence increases in mouse models. This advancement has created the brightest and most sensitive luciferase-luciferin combination, enabling high-speed video-rate imaging of freely moving mice with brain-expressed luciferase. These innovative substrates offer new possibilities for investigating a wide range of biological processes and are poised to become invaluable resources for chemical, biological, and biomedical fields.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"128-136"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Click Chemistry Methodology: The Novel Paintbrush of Drug Design.","authors":"Ioana Oprea, Terry K Smith","doi":"10.1021/acschembio.4c00608","DOIUrl":"10.1021/acschembio.4c00608","url":null,"abstract":"<p><p>Click chemistry is an immensely powerful technique for the synthesis of reliable and efficient covalent linkages. When undertaken in living cells, the concept is thereby coined bioorthogonal chemistry. Used in conjunction with the photo-cross-linking methodology, it serves as a sound strategy in the exploration of biological processes and beyond. Its broad scope has led to widespread use in many disciplines; however, this Review focuses on the use of click and bioorthogonal chemistry within medicinal chemistry, specifically with regards to drug development applications, namely, the use of DNA-encoded libraries as a novel technique for lead compound discovery, as well as the synthesis of antisense oligonucleotides and protein-drug conjugates. This Review aims to provide a critical perspective and a future outlook of this methodology, such as potential widespread use in cancer therapy and personalized medicine.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"19-32"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2-Cyanopyrimidine-Containing Molecules for N-Terminal Selective Cyclization of Phage-Displayed Peptides.","authors":"J Trae Hampton, Connor R Dobie, Demonta D Coleman, Moulay I Cherif, Sukant Das, Wenshe Ray Liu","doi":"10.1021/acschembio.4c00725","DOIUrl":"10.1021/acschembio.4c00725","url":null,"abstract":"<p><p>Current methods for the macrocyclization of phage-displayed peptides often rely on small molecule linkers that nonspecifically react with targeted amino acid residues. To expand tool kits for more regioselective macrocyclization of phage-displayed peptides, this study explores the unique condensation reaction between an N-terminal cysteine and nitrile along with the reactivity of an internal cysteine. Five 2-cyanopyrimidine derivatives were synthesized for this purpose and evaluated for their selective macrocyclization of a protein-fused model peptide. Among these, two novel linkers, 2-chloro-<i>N</i>-(2-cyanopyrimidin-5-yl)acetamide (pCAmCP) and 2-chloro-<i>N</i>-(2-cyanopyrimidin-4-yl)acetamide (mCAmCP), emerged as efficient molecules and were demonstrated to macrocyclize phage-displayed peptide libraries flanked by an N-terminal and an internal cysteine. Using these linkers to generate macrocyclic peptide libraries displayed on phages, peptide ligands for the ZNRF3 extracellular domain were successfully identified. One of the identified peptides, Z27S1, exhibited potent binding to ZNRF3 with a <i>K</i>_D value of 360 nM. Notably, the selection results revealed distinct peptide enrichment patterns depending on whether mCAmCP or pCAmCP was used, underscoring the significant impact of linker choice on macrocyclic peptide identification. Overall, this study validates the development of two novel regioselective, small molecule linkers for phage display of macrocyclic peptides and highlights the benefits of employing multiple linkers during phage selections.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"219-228"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescent d-amino Acid-Based Approach Enabling Fast and Reliable Measure of Antibiotic Susceptibility in Bacterial Cells.","authors":"Barbara Walenkiewicz, Michael S VanNieuwenhze","doi":"10.1021/acschembio.4c00639","DOIUrl":"10.1021/acschembio.4c00639","url":null,"abstract":"<p><p>The threat of multidrug-resistant bacteria has been increasing steadily in the past century, posing a major health risk (Organización Mundial de la Salud. Directrices Sobre Componentes Básicos Para Los Programas de Prevención y Control de Infecciones a Nivel Nacional y de Establecimientos de Atención de Salud Para Pacientes Agudos; Organización Mundial de la Salud: Ginebra, <b>2017</b>). Even though every year, 226 million antibiotics are prescribed in the United States alone, 50% of these prescriptions are inappropriate for the patient's condition (CDC. Get Smart about Antibiotics Week; Centers for Disease Control and Prevention. <b>2016</b>,https://www.cdc.gov/media/dpk/antibiotic-resistance/antibiotics-week-2016/dpk-antibiotics-week-2016.html). The increasing abuse of antibiotics in healthcare as well as agriculture has resulted in the rise of antibiotic resistance at an alarming rate. In a clinical setting, timely and accurate recognition of the pathogen allows for the most effective choice of treatment, highlighting the need for novel, fast, and reliable antibiotic susceptibility testing. Traditional susceptibility testing techniques require costly and complex experimental setups or extended cell incubation periods, delaying a timely treatment response to the infection. Herein, we report that a short-pulse fluorescent d-amino acid (FDAA)-based approach provides insight not only into bacterial antibiotic susceptibility but also into the mechanism of action of the antibiotic. Using the FDAA-labeling signal as a reflection of peptidoglycan (PG) integrity after antibiotic treatment, we observed that drugs targeting PG biosynthesis resulted in a significant decrease in fluorescence, while antimicrobials affecting other cellular targets resulted in no fluorescence changes. Our method was validated and optimized via fluorescence microscopy and spectrofluorometry, shortening the required procedure time to 15 min and providing reliably reproducible results. Significantly, we demonstrate that our protocol can be used to identify β-lactam-resistant bacterial strains, further demonstrating the utility of these valuable molecular tools.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"162-171"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tudor-Containing Methyl-Lysine and Methyl-Arginine Reader Proteins: Disease Implications and Chemical Tool Development.","authors":"Mélanie Uguen, Tongkun Liu, Lindsey I James, Stephen V Frye","doi":"10.1021/acschembio.4c00661","DOIUrl":"10.1021/acschembio.4c00661","url":null,"abstract":"<p><p>Tudor domains are histone readers that can recognize various methylation marks on lysine and arginine. This recognition event plays a key role in the recruitment of other epigenetic effectors and the control of gene accessibility. The Tudor-containing protein family contains 42 members, many of which are involved in the development and progression of various diseases, especially cancer. The development of chemical tools for this family will not only lead to a deeper understanding of the biological functions of Tudor domains but also lay the foundation for therapeutic discoveries. In this review, we discuss the role of several Tudor domain-containing proteins in a range of relevant diseases and progress toward the development of chemical tools such as peptides, peptidomimetics, or small-molecules that bind Tudor domains. Overall, we highlight how Tudor domains are promising targets for therapeutic development and would benefit from the development of novel chemical tools.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"33-47"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Class A/B Hybrid GPCR System for the Proximity-Assisted Screening of GPCR Ligands.","authors":"Monika T Gnatzy, Steffen Hartmann, Felix Hausch","doi":"10.1021/acschembio.4c00658","DOIUrl":"10.1021/acschembio.4c00658","url":null,"abstract":"<p><p>Class A G protein-coupled receptors (GPCRs) are key mediators in numerous signaling pathways and important drug targets for several diseases. A major shortcoming in GPCR ligand screening is the detection limit for weak binding molecules, which is especially critical for poorly druggable GPCRs. Here, we present a proximity-based screening system for class A GPCRs, which adopts the natural two-step activation mechanism of class B GPCRs. In this approach, class A/B chimeras with the extracellular domain of the class B receptor CRF₁R grafted to the transmembrane domain of target class A receptors are stimulated with hybrid ligands. These ligands contain a high-affinity peptide derived from CRF, which recruits the hybrid ligands to the engineered target GPCR, dramatically increasing the local concentration of the test substances. We exemplified this method for neurotensin receptor 1 (NTR₁) and endothelin receptor B (ET_B), two important class A GPCR drug targets for pulmonary arterial hypertension or psychological disorders and neurodegenerative diseases. We observed >20× activity enhancement by the directed proximity approach, enabling the detection of weakly activating sequences that would have otherwise remained undetected. Our approach allows to probe GPCR activation in the membrane of living cells and may be especially useful for GPCRs for which it has been difficult to generate small drug-like molecules.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"172-178"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tailored Bisacylphosphane Oxides for Precise Induction of Oxidative Stress-Mediated Cell Death in Biological Systems.","authors":"Karim Almahayni, Jana Bachir Salvador, Riccardo Conti, Anna Widera, Malte Spiekermann, Daniel Wehner, Hansjörg Grützmacher, Leonhard Möckl","doi":"10.1021/acschembio.4c00399","DOIUrl":"10.1021/acschembio.4c00399","url":null,"abstract":"<p><p>Precise cell elimination within intricate cellular populations is hampered by issues arising from the multifaceted biological properties of cells and the expansive reactivity of chemical agents. Current chemical platforms are often limited by their complexity, toxicity, and poor physical/chemical properties. Here, we report on the synthesis of a structurally versatile library of chemically tunable bisacylphosphane oxides (BAPOs), which harnesses the spatiotemporal precision of light delivery, thereby establishing a universal strategy for on-demand, precise cellular ablation <i>in vitro</i> and <i>in vivo</i>.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"77-85"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}