Review
Chemistry, Multidisciplinary
Yue Huang, Wenyang Xia, Ze Dong, Cai-Guang Yang
Summary: Epigenetics, including the N-6-methyladenosine (m(6)A) modification, plays a critical role in gene expression regulation. Understanding the biology of RNA epigenetics and developing drugs targeting m(6)A modifying proteins is important for cancer research and therapy.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Article
Genetics & Heredity
Chiara Siniscalchi, Armando Di Palo, Aniello Russo, Nicoletta Potenza
Summary: This study identified specific cellular miRNAs that interact with SARS-CoV-2 sequences, demonstrating experimental evidence of their binding and potential therapeutic implications. The interaction between miRNAs and viral sequences was validated through luciferase reporter assays, offering insights into the molecular mechanisms underlying virus infection and potential therapeutic interventions. The study also highlighted the conservation of viral target sequences in recent variants, suggesting the importance of targeting these miRNAs for developing innovative diagnostic tools and interventions.
FRONTIERS IN GENETICS
(2021)
Article
Biology
Marcela A. Cucher, Mara Mariconti, Tommaso Manciulli, Ambra Vola, Mara C. Rosenzvit, Klaus Brehm, Laura Kamenetzky, Enrico Brunetti
Summary: Currently, AE and CE are diagnosed by imaging techniques, serology, and clinical and epidemiological data. However, no viability markers are available for parasite state during infection. Extracellular small RNAs (sRNAs) have been studied as biomarkers for diseases, and profiling the sRNA transcriptomes of AE and CE patients can help identify novel biomarkers for medical decisions.
Article
Biochemistry & Molecular Biology
Jung Woo Eun, Hye Ri Ahn, Geum Ok Baek, Moon Gyeong Yoon, Ju A. Son, Ji Hyang Weon, Jung Hwan Yoon, Hyung Seok Kim, Ji Eun Han, Soon Sun Kim, Jae Youn Cheong, Bong-wan Kim, Hyo Jung Cho
Summary: Cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC) have downregulated expression of hsa-miR-101-3p and hsa-miR-490-3p, which target TGFBR1. The downregulation of these miRs and high TGFBR1 expression are associated with poor prognosis in HCC patients. TGFBR1 expression is also correlated with infiltration of immunosuppressive immune cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Ji Young Yoo, Margaret Yeh, Balveen Kaur, Tae Jin Lee
Summary: Aberrant gene and miRNA expression can drive cancer development, and the modulation of these expressions provides a therapeutic opportunity. Recent advances in RNA nanotechnology offer potential for miRNA therapy, but the lack of a delivery platform remains a challenge.
Review
Biochemistry & Molecular Biology
Caroline Diener, Andreas Keller, Eckart Meese
Summary: This review summarizes key features of mammalian miRNA-target interactions (MTIs), including dynamic composition of miRNA binding sites, cooperativity between miRNA binding sites, adaptivity of MTIs through sequence modifications, impact of intra-cellular miRNA localization changes, and the role of cell type and cell status specific miRNA interaction partners. The article also discusses experimental strategies for evaluating miRNA functionality.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Chemistry, Multidisciplinary
James P. Falese, Anita Donlic, Amanda E. Hargrove
Summary: This article reviews recent advances in understanding RNA biology, including its crucial roles in various disease states and the challenges and methods for drug design targeting RNA. It focuses on discussing RNA structural hierarchy, functional classes, and dynamics, as well as methods for small molecule screening and RNA structure determination. Finally, it summarizes the unique challenges and emerging solutions for generating RNA-targeted ligands from both RNA and small molecule perspectives.
CHEMICAL SOCIETY REVIEWS
(2021)
Review
Cell Biology
Amirreza Bitaraf, Ehsan Razmara, Babak Bakhshinejad, Hassan Yousefi, Mousa Vatanmakanian, Masoud Garshasbi, William C. Cho, Sadegh Babashah
Summary: Posttranscriptional regulation involving RNA-binding proteins (RBPs) plays a crucial role in the initiation and progression of tumorigenesis by controlling gene expression at the RNA level. RBPs influence the malignant transformation of cancer cells through mechanisms such as alternative splicing, stability, polyadenylation, localization, and translation. Additionally, interactions between RBPs and other posttranscriptional regulators like microRNAs and long noncoding RNAs are important in the pathogenesis of cancer.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Article
Plant Sciences
Gigi Y. Wong, Anthony A. Millar
Summary: In plants, the relationships between microRNAs (miRNAs) and their target genes are complex, with predictions indicating numerous and diverse targets based on complementarity. However, there is also a hypothesis suggesting that miRNA specificity is constrained and limited to a few targets with compatible expression. To explore these opposing views, a bioinformatic pipeline was used to identify highly conserved miRNA targets across species. The results supported the constrained hypothesis, showing that the majority of miRNA targets belong to conserved target gene families, with a minority of secondary families or non-conserved targets.
PLANT AND CELL PHYSIOLOGY
(2023)
Article
Oncology
Jinqin Chen, Chengpeng Gao, Wei Zhu
Summary: SLC25A25-AS1 exerts tumor-promoting roles in non-small cell lung cancer (NSCLC) by controlling the miR-195-5p/ITGA2 axis. High expression of SLC25A25-AS1 is significantly associated with shorter overall survival time in NSCLC patients, and its silencing can inhibit malignant behaviors of NSCLC cells.
Article
Multidisciplinary Sciences
Elena Menichelli, Bianca J. Lam, Yu Wang, Vivian S. Wang, Jennifer Shaffer, Katrina F. Tjhung, Badry Bursulaya, Truc Ngoc Nguyen, Todd Vo, Phillip B. Alper, Christopher S. McAllister, David H. Jones, Glen Spraggon, Pierre-Yves Michellys, John Joslin, Gerald F. Joyce, Jeff Rogers
Summary: There is growing interest in using small molecules to target disease-relevant RNAs in therapeutic intervention. However, the understanding of structure-activity relationships in pursuing RNA targets is limited. This study identified several unique compounds through high-throughput screening that bind to a well-studied RNA structure, the theophylline aptamer, with significantly higher affinity than theophylline itself. The atomic-resolution X-ray crystal structures of these compounds revealed the rigidity of the RNA binding pocket and the potential for other ligands to bind more tightly. These findings suggest that the same approaches used for protein drug discovery can also be applied to RNA.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Livia Fratini, Mariane Jaeger, Caroline Brunetto de Farias, Andre T. Brunetto, Algemir L. Brunetto, Lisa Shaw, Rafael Roesler
Summary: The transcription factor ZEB1 plays a critical role in cell function and embryonic development, with its activities regulated by interactions with miRNAs and lncRNAs. While the exact role of ZEB1 in pediatric cancer is still unclear, emerging evidence suggests its involvement in regulating solid tumors in children.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2021)
Article
Genetics & Heredity
Bo Guo, Wen Li, Yijie Liu, Dehui Xu, Zhijie Liu, Chen Huang
Summary: Our study found that 28 miRNAs were significantly altered in chroni myeloid leukemia K562 cells treated with a room-temperature argon plasma jet for 90 s after 24 h, with 17 upregulated and 11 downregulated. GO enrichment analysis revealed that the target genes were related to cell organelles, protein binding, and single-organism processes. KEGG pathway analysis demonstrated that the target genes of differentially expressed miRNAs were primarily involved in the cAMP signaling pathway, AMPK signaling pathway, and phosphatidylinositol signaling system.
FRONTIERS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Quinlin M. Hanson, Nate Hoxie, Min Shen, Hui Guo, Ig-Jun Cho, Ipsita Chakraborty, Brooklyn M. Aragon, Ganesha Rai, Samarjit Patnaik, John S. Janiszewski, Matthew D. Hall
Summary: Target class profiling (TCP) is a chemical biology approach to investigate understudied biological target classes. In this study, TCP was used to investigate inhibitory activity of small-molecule methyltransferases (SMMTases), and a novel inhibitor was discovered for the SMMTase HNMT.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Quinlin M. Hanson, Nate Hoxie, Min Shen, Hui Guo, Ig-Jun Cho, Ipsita Chakraborty, Brooklyn M. Aragon, Ganesha Rai, Samarjit Patnaik, John S. Janiszewski, Matthew D. Hall
Summary: Target class profiling (TCP) is a chemistry biology approach used to investigate understudied biological targets. By developing a generalizable assay platform and screening curated compound libraries, TCP explores the chemical biological space of enzyme families. In this study, TCP was used to investigate inhibitory activity in a set of small-molecule methyltransferases (SMMTases) in order to explore this relatively unexplored target class. High-throughput screening (HTS)-amenable assays were optimized to screen a large number of small molecules against representative SMMTases, resulting in the identification of a novel inhibitor for the SMMTase HNMT.
ACS CHEMICAL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Jessica A. Bush, Christopher C. Williams, Samantha M. Meyer, Yuquan Tong, Hafeez S. Haniff, Jessica L. Childs-Disney, Matthew D. Disney
Summary: The manipulation of biological systems by small molecules is a powerful approach in chemical biology, with a focus on targeting RNA as an attractive therapeutic alternative. The systematic evaluation of target validation and modulation of target-associated pathways is of paramount importance as the field of RNA chemical biology emerges. Through case studies, the impact of small molecules that target RNA on cellular phenotype is comprehensively evaluated in this Review.
ACS CHEMICAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Jared T. Baisden, Jessica L. Childs-Disney, Lucas S. Ryan, Matthew D. Disney
Summary: The ENCODE and genome-wide association projects have found that most of the genome is transcribed into RNA, with the druggable transcriptome being larger than the druggable proteome. Strategies to target RNA and the unique modes of action suggest that RNAs are potentially more amenable to targeting than proteins.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Sarah Wagner-Griffin, Masahito Abe, Raphael Benhamou, Alicia J. Angelbello, Kamalakannan Vishnu, Jonathan L. Chen, Jessica L. Childs-Disney, Matthew D. Disney
Summary: This study presents druglike small molecules that bind and improve defects associated with DM2 by targeting the RNA repeat expansion. Through optimization of small molecules binding the structure adopted by r(CCGU)(exp), endogenous degradation of the aberrantly retained intron, and rescue of alternative splicing defects are achieved.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Editorial Material
Chemistry, Multidisciplinary
Matthew D. Disney
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Raphael Benhamou, Shruti Choudhary, Elizabeth Lekah, Yuquan Tong, Matthew D. Disney
Summary: Studies have shown that selective molecular recognition of RNA targets by small molecules in cells is possible, with one strategy being the simultaneous binding of two or more sites within RNA with a single molecule. By informatically mining human miRNA precursors, targets amenable to small molecule targeting can be identified, with oncogenic miRNA-27a being a lead molecule that can inhibit miRNA processing in cancer cells. This demonstrates that a synergistic approach involving bioinformatics and experimental methods can define suitable targets for small molecule targeting.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Andrei Ursu, Jared T. Baisden, Jessica A. Bush, Amirhossein Taghavi, Shruti Choudhary, Yong-Jie Zhang, Tania F. Gendron, Leonard Petrucelli, Ilyas Yildirim, Matthew D. Disney
Summary: A small molecule (CB253) has been discovered to selectively bind the hairpin form of the hexanucleotide repeat expansion RNA in c9ALS/FTD patients, shifting the equilibrium towards a different internal loop conformation and inhibiting pathogenic mechanisms.
ACS CHEMICAL NEUROSCIENCE
(2021)
Review
Biotechnology & Applied Microbiology
Jessica L. Childs-Disney, Xueyi Yang, Quentin M. R. Gibaut, Yuquan Tong, Robert T. Batey, Matthew D. Disney
Summary: Disney and colleagues review strategies for identifying, validating, and optimizing small-molecule RNA binders, and discuss challenges and future directions in the field.
NATURE REVIEWS DRUG DISCOVERY
(2022)
Article
Chemistry, Multidisciplinary
Blessy M. Suresh, Yoshihiro Akahori, Amirhossein Taghavi, Gogce Crynen, Quentin M. R. Gibaut, Yue Li, Matthew D. Disney
Summary: By constructing a comprehensive RNA-focused small-molecule fragment collection and studying the binding landscape of different fragments to RNA experimentally, a potent and specific drug-like fragment targeting a specific RNA target was discovered, showing promising application in alleviating oncogenic features of certain cancer cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Quentin M. R. Gibaut, Yoshihiro Akahori, Jessica A. Bush, Amirhossein Taghavi, Toru Tanaka, Haruo Aikawa, Lucas S. Ryan, Brian M. Paegel, Matthew D. Disney
Summary: In this study, a solid-phase DNA-encoded library (DEL) was used to identify and optimize RNA binders for adult-onset muscular dystrophy. One binder was found to specifically bind the causative agent and improved disease-associated defects by attaching it with a module that cleaves the agent.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Medicinal
Blessy M. Suresh, Amirhossein Taghavi, Jessica L. Childs-Disney, Matthew D. Disney
Summary: Although there are challenges in fragment-based drug discovery (FBDD) for RNA targets, some bioactive ligands have been identified by integrating known methods of RNA binder discovery with fragment-based approaches. This review discusses various fragment-based approaches for RNA targets, providing insights into experimental design and outcomes for future research. Investigations into the molecular recognition of RNA by fragments address important questions such as the limits of molecular weight for selective binding and the physicochemical properties favorable for RNA binding and bioactivity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Samantha M. Meyer, Toru Tanaka, Amirhossein Taghavi, Jared T. Baisden, Maison Grefe, Matthew D. Disney
Summary: This study designs molecules that specifically inhibit RNA targets without affecting canonical protein targets, based on knowledge of the molecular recognition of both protein and RNA targets by dovitinib.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Blessy M. Suresh, Yuquan Tong, Daniel Abegg, Alexander Adibekian, Jessica L. Childs-Disney, Matthew D. Disney
Summary: This study investigates the factors affecting the degradation of two cancer-associated RNA targets and explores how structural features can be leveraged to program selective small-molecule degradation. The findings have important implications for the development of chemical probes and potential lead medicines targeting RNA.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Xueyi Yang, Jessica L. Childs-Disney, M. Paegel, Matthew D. Disney
Summary: The functional roles of structured RNAs in biological processes are now being recognized, leading to the potential of RNA as a therapeutic target. Robust and high-throughput methods for identifying potent RNA ligands are crucial for developing chemical probes and therapeutics. The use of DNA-encoded libraries (DEL) technology has emerged as a powerful tool for discovering protein ligands and offers unprecedented opportunities for designing RNA ligands. In this review, we discuss the principles of DEL selection, the progress made in targeting RNA using DEL, and the future outlook.
ISRAEL JOURNAL OF CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Quentin M. R. Gibaut, Jessica A. Bush, Yuquan Tong, Jared T. Baisden, Amirhossein Taghavi, Hailey Olafson, Xiyuan Yao, Jessica L. Childs-Disney, Eric T. Wang, Matthew D. Disney
Summary: This study introduces a pipeline to identify and eliminate the r(CUG) repeat expansion causing DM1 in cells.
ACS CENTRAL SCIENCE
(2023)
Editorial Material
Clinical Neurology
Rita Sattler, Bryan J. Traynor, Janice Robertson, Ludo Van den Bosch, Sami J. Barmada, Clive N. Svendsen, Matthew D. Disney, Tania F. Gendron, Philip C. Wong, Martin R. Turner, Adam Boxer, Suma Babu, Michael Benatar, Michael Kurnellas, Jonathan D. Rohrer, Christopher J. Donnelly, Lynette M. Bustos, Kendall Van Keuren-Jensen, Penny A. Dacks, Marwan N. Sabbagh
Summary: The summit highlighted the role of the C9ORF72 gene in FTD and ALS, covering disease mechanisms, therapeutic strategies, and biomarkers. Collaborative efforts aimed to break down existing disease silos and proposed composite endpoints for evaluating treatments covering clinical symptoms.
NEUROLOGY AND THERAPY
(2023)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)