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Targeting rna with Small Molecules: Identification of Selective, rna-Binding Small Molecules Occupying Drug-Like Chemical Space

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SLAS DISCOVERY 2020年第4期25卷 384-396页

作者： Rizvi, Noreen F. Santa Maria, John P., Jr. Nahvi, Ali Klappenbach, Joel Klein, Daniel J. Curran, Patrick J. Richards, Matthew P. Chamberlin, Chad Saradjian, Peter Burchard, Julja Aguilar, Rodrigo Lee, Jeannie T. Dandliker, Peter J. Smith, Graham F. Kutchukian, Peter Nickbarg, Elliott B. Merck & Co Inc 33 Ave Louis Pasteur Boston MA 02115 USA Merck & Co Inc West Point PA USA Massachusetts Gen Hosp Dept Mol Biol Boston MA 02114 USA Harvard Med Sch Blavatnik Inst Dept Genet Boston MA 02115 USA

Although the potential value of rna as a target for new small molecule therapeutics is becoming increasingly credible, the physicochemical properties required for small molecules to selectively bind to rna remain relatively unexplored. To investigate the druggability of rnas with small molecules, we have employed affinity mass spectrometry, using the Automated Ligand Identification System (ALIS), to screen 42 rnas from a variety of rna classes, each against an array of chemically diverse drug-like small molecules (similar to 50,000 compounds) and functionally annotated tool compounds (similar to 5100 compounds). The set of rna-small molecule interactions that was generated was compared with that for protein-small molecule interactions, and naive Bayesian models were constructed to determine the types of specific chemical properties that bias small molecules toward binding to rna. This set of rna-selective chemical features was then used to build an rna-focused set of similar to 3800 small molecules that demonstrated increased propensity toward binding the rna target set. In addition, the data provide an overview of the specific physicochemical properties that help to enable binding to potential rna targets. This work has increased the understanding of the chemical properties that are involved in small molecule binding to rna, and the methodology used here is generally applicable to rna-focused drug discovery efforts.

关键词： rna noncoding rna drug screening drug target mass spectrometry

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Bioengineered rna Therapy in Patient-Derived Organoids and Xenograft Mouse Models

Bioengineered RNA Therapy in Patient-Derived Organoids and X...

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作者： Mei-Juan Tu Colleen M. Yi Gavin M. Traber Ai-Ming Yu

Therapeutic rnas, such as antisense oligonucleotides (ASOs), aptamers, small-interfering rnas (sirnas), micrornas (miRs or mirnas), messenger rnas (mrnas), and guide rnas (grnas), represent a novel class of modalities that not only increase the molecular diversity of medications but also expand the range of druggable targets. To develop noncoding rna therapeutics for the treatment of cancer diseases, we have established a novel robust rna bioengineering platform to achieve high-yield and large-scale production of true biologic rna agents, which are proven to be functional in the control of target gene expression and effective in the management of tumor progression in various models. Herein, we describe the methods for bioengineered rna (Biorna or BERA) therapy in patient-derived organoids (PDOs) in vitro and patient-derived xenograft (PDX) mouse models in vivo. The efficacy of a Biorna, miR-1291, in the inhibition of pancreatic cancer PDO and PDX growth is exemplified in this chapter. less

关键词： 3D Cell Culture Cell And Tissue Culture Organoid Culture Chromatography Cell Proliferation Assay Intraperitoneal Injection rna Purification Mus musculus HEK293T L Wnt-3A PDX Cancer sirna microrna noncoding rna Therapy Bioengineer PDO

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Assessing circular rnas in Alzheimer ?s disease and frontotemporal lobar degeneration

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NEUROBIOLOGY OF AGING 2020年 92卷 7-11页

作者： Cervera-Carles, Laura Dols-Icardo, Oriol Molina-Porcel, Laura Alcolea, Daniel Cervantes-Gonzalez, Alba Munoz-Llahuna, Laia Clarimon, Jordi Univ Autonoma Barcelona St Pau Biomed Res Inst Genet Neurodegenerat Disorders Unit Hosp Santa Creu & St Pau Barcelona Spain Ctr Networked Biomed Res Neurodegenerat Dis CIBERNED Madrid Spain Inst Invest Biomed August Pi I Sunyer Neurol Tissue Bank Biobanc Hosp Clin IDIBAPS Barcelona Spain Univ Autonoma Barcelona Hosp Santa Creu & St Pau Neurobiol Dementias Unit St Pau Biomed Res Inst Barcelona Spain

A circular-transcriptome-wide study has recently linked differential expression of circular rnas (circrnas) in brain tissue with Alzheimer’s disease (AD). We aimed at replicating the major findings in an independent series of sporadic and familial AD. We also included cases with frontotemporal lobar degeneration (FTLD), comprising brain specimens with TDP-43 aggregates (FTLD-TDP43) and samples that presented Tau accumulation (FTLD-Tau). Using a quantitative polymerase chain reaction approach, we evaluated 8 circrnas that surpassed the significant threshold in the former meta-analysis (circHOMER1, circDOCK1, circFMN1, circKCNN2, circRTN4, circMAN2A1, circMAP7, and circPICALM). Average expression changes between patients with AD and controls followed the same directions as previously reported. We also confirmed an exacerbated alteration in circrna expression in the familial AD group compared with the sporadic forms. Two circrnas (circHOMER1 and circKCNN2) also showed significant expression alterations in the group of FTLD-Tau and FTLD-TDP43, respectively. Overall, these results reinforce the conception that expression of circrnas is different in AD, and also suggest a wider involvement of this particular class of rna in other neurodegenerative dementias.

关键词： Alzheimer’s disease circrna noncoding rna Genetics Frontotemporal lobar degeneration

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Human Argonaute2 and Argonaute3 are catalytically activated by different lengths of guide rna

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2020年第46期117卷 28576-28578页

作者： Park, Mi Seul Sim, GeunYoung Kehling, Audrey C. Nakanishi, Kotaro Ohio State Univ Dept Chem & Biochem Columbus OH 43210 USA Ohio State Univ Ctr RNA Biol Columbus OH 43210 USA Ohio State Univ Mol Cellular & Dev Biol Columbus OH 43210 USA

rna interfering is a eukaryote-specific gene silencing by 20-23 nucleotide (nt) micrornas and small interfering rnas that recruit Argonaute proteins to complementary rnas for degradation. In humans, Argonaute2 (AGO2) has been known as the only slicer while Argonaute3 (AGO3) barely cleaves rnas. Therefore, the intrinsic slicing activity of AGO3 remains controversial and a longstanding question. Here, we report 14-nt 3 ' end-shortened variants of let-7a, miR-27a, and specific miR-17-92 families that make AGO3 an extremely competent slicer, increasing target cleavage up to-82-fold in some instances. These rnas, named cleavageinducing tiny guide rnas (cityrnas), conversely lower the activity of AGO2, demonstrating that AGO2 and AGO3 have different optimum guide lengths for target cleavage. Our study sheds light on the role of tiny guide rnas.

关键词： rnai Argonaute noncoding rna enzyme

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Telomerasernaprocessing: Implications for human health and disease

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STEM CELLS 2020年第12期38卷 1532-1543页

作者： Nagpal, Neha Agarwal, Suneet Boston Childrens Hosp Div Hematol Oncol Boston MA USA Boston Childrens Hosp Stem Cell Program Boston MA USA Dana Farber Canc Inst Pediat Oncol Boston MA 02115 USA Harvard Med Sch Harvard Initiat RNA Med Boston MA 02115 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Harvard Stem Cell Inst Boston MA USA

Telomeres are composed of repetitive DNA sequences that are replenished by the enzyme telomerase to maintain the self-renewal capacity of stem cells. The rna component of human telomerase (TERC) is the essential template for repeat addition by the telomerase reverse transcriptase (TERT), and also serves as a scaffold for several factors comprising the telomerase ribonucleoprotein (RNP). Unique features of TERC regulation and function have been informed not only through biochemical studies but also through human genetics. Disease-causing mutations impact TERC biogenesis at several levels including rna transcription, post-transcriptional processing, folding, RNP assembly, and trafficking. Defects in TERC reduce telomerase activity and impair telomere maintenance, thereby causing a spectrum of degenerative diseases called telomere biology disorders (TBDs). Deciphering mechanisms of TERC dysregulation have led to a broader understanding of noncoding rna biology, and more recently points to new therapeutic strategies for TBDs. In this review, we summarize over two decades of work revealing mechanisms of human telomerase rna biogenesis, and how its disruption causes human diseases.

关键词： dyskeratosis congenita dyskerin noncoding rna stem cells telomere TERC TERT

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Phase separation drives pairing of homologous chromosomes

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CURRENT GENETICS 2020年第5期66卷 881-887页

作者： Hiraoka, Yasushi Osaka Univ Grad Sch Frontier Biosci 1-3 Yamadaoka Suita Osaka 5650871 Japan

Pairing of homologous chromosomes is crucial for ensuring accurate segregation of chromosomes during meiosis. Molecular mechanisms of homologous chromosome pairing in meiosis have been extensively studied in the fission yeast Schizosaccharomyces pombe. In this organism, meiosis-specific noncoding rna transcribed from specific genes accumulates at the respective gene loci, and chromosome-associated rna-protein complexes mediate meiotic pairing of homologous loci through phase separation. Pairing of homologous chromosomes also occurs in somatic diploid cells in certain situations. For example, somatic pairing of homologous chromosomes occurs during the early embryogenesis in diptera, and relies on the transcription-associated chromatin architecture. Earlier models also suggest that transcription factories along the chromosome mediate pairing of homologous chromosomes in plants. These studies suggest that rna bodies formed on chromosomes mediate the pairing of homologous chromosomes. This review summarizes lessons from S. pombe to provide general insights into mechanisms of homologous chromosome pairing mediated by phase separation of chromosome-associated rna-protein complexes.

关键词： Fission yeast Homologous chromosome noncoding rna Phase separation

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rna Structure Prediction, Analysis, and Design: An Introduction to Web-Based Tools

RNA Structure Prediction, Analysis, and Design: An Introduct...

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作者： Raphael Angelo Zambrano Carmen Hernandez-Perez Melissa K. Takahashi

Understanding rna structure has become critical in the study of rna in their roles as mediators of biological processes. To aid in these studies, computational algorithms that utilize thermodynamics have been developed to predict rna secondary structure. Due to the importance of intermolecular interactions, the algorithms have been expanded to determine and predict rna-rna hybridization. This chapter discusses popular webservers with the tools for rna secondary structure prediction, rna-rna hybridization, and design. We address key features that distinguish common-functioning programs and their purposes for the interests of the user. Ultimately, we hope this review elucidates web-based tools researchers may take advantage of in their investigations of rna structure and function. less

关键词： rna Secondary Structure Prediction rna Structure Prediction noncoding rna rna design tools

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Lncrna Lnc-APUE is Repressed by HNF4α and Promotes G1/S Phase Transition and Tumor Growth by Regulating MiR-20b/E2F1 Axis

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ADVANCED SCIENCE 2021年第7期8卷 2003094页

作者： Li, Song-Yang Zhu, Ying Li, Ruo-Nan Huang, Jia-Hui You, Kai Yuan, Yun-Fei Zhuang, Shi-Mei Sun Yat Sen Univ MOE Key Lab Gene Funct & Regulat Sch Life Sci Collaborat Innovat Ctr Canc Med Guangzhou 510275 Peoples R China Sun Yat Sen Univ Dept Hepatobilliary Oncol Ctr Canc Guangzhou 510060 Peoples R China

Many long noncoding rnas (lncrnas) have been annotated, but their functions remain unknown. The authors found a novel lnc-APUE (lncrna accelerating proliferation by upregulating E2F1) that is upregulated in different cancer types, including hepatocellular carcinoma (HCC), and high lnc-APUE level is associated with short recurrence-free survival (RFS) of HCC patients. Gain- and loss-of-function analyses showed that lnc-APUE accelerated G1/S transition and tumor cell growth in vitro and allows hepatoma xenografts to grow faster in vivo. Mechanistically, lnc-APUE binds to miR-20b and relieves its repression on E2F1 expression, resulting in increased E2F1 level and accelerated G1/S phase transition and cell proliferation. Consistently, lnc-APUE level is positively associated with the expression of E2F1 and its downstream target genes in HCC tissues. Further investigations disclose that hepatocyte nuclear factor 4 alpha (HNF4 alpha) binds to the lnc-APUE promoter, represses lnc-APUE transcription, then diminishes E2F1 expression and cell proliferation. HNF4 alpha expression is reduced in HCC tissues and low HNF4 alpha level is correlated with high lnc-APUE expression. Collectively, a HNF4 alpha/lnc-APUE/miR-20b/E2F1 axis in which HNF4 alpha represses lnc-APUE expression and keeps E2F1 at a low level is identified. In tumor cells, HNF4 alpha downregulation leads to lnc-APUE upregulation, which prevents the inhibition of miR-20b on E2F1 expression and thereby promotes cell cycle progression and tumor growth.

关键词： cell cycle cerna hepatocellular carcinoma lnc-APUE noncoding rna

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Computational Detection of Microrna Targets

Computational Detection of MicroRNA Targets

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作者： Pedro Gabriel Nachtigall Luiz Augusto Bovolenta

Micrornas (mirnas) are small noncoding rnas that are recognized as posttranscriptional regulators of gene expression. These molecules have been shown to play important roles in several cellular processes. Mirnas act on their target by guiding the RISC complex and binding to the mrna molecule. Thus, it is recognized that the function of a mirna is determined by the function of its target (s). By using high-throughput methodologies, novel mirnas are being identified, but their functions remain uncharted. Target validation is crucial to properly understand the specific role of a mirna in a cellular pathway. However, molecular techniques for experimental validation of mirna–target interaction are expensive, time-consuming, laborious, and can be not accurate in inferring true interactions. Thus, accurate mirna target predictions are helpful to understand the functions of mirnas. There are several algorithms proposed for target prediction and databases containing mirna-target information. However, these available computational tools for prediction still generate a large number of false positives and fail to detect a considerable number of true targets, which indicates the necessity of highly confident approaches to identify bona fide mirna–target interactions. This chapter focuses on tools and strategies used for mirna target prediction, by providing practical insights and outlooks. less

关键词： Bioinformatics Computational biology noncoding rna mirna recognition element Target prediction tools

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CRISPR-Cas9 Editing of the

CRISPR-Cas9 Editing of the

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作者： Xu Zhang Kirk William Deitsch Ron Dzikowski

The virulence of Plasmodium falciparum has been attributed in large part to the expression on the surface of infected red blood cells of the variant surface antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Different forms of this protein are encoded by individual members of the multicopy gene family called var. Two attributes of the var gene family are key to the pathogenesis of malaria caused by P. falciparum; the hyperrecombinogenic nature of the var gene family that continuously generates antigenic diversity within parasite populations, and the ability of parasites to express only a single var gene at a time and to switch which gene is expressed over the course of an infection. The unique attributes of CRISPR-Cas9 have been applied to help decipher the molecular mechanisms underlying these unusual properties of the var gene family, both as a source of the DNA double strand breaks that initiate var gene recombination and as a way to recruit molecular probes to specific regions of the genome. In this chapter, we describe these somewhat unusual applications of the CRISPR-Cas9 system. less

关键词： CRISPR-Cas9 Genome Editing Parasite Culture Transfection Electroporation Microscopy Genome Editing Real-time PCR PCR Whole-genome Sequencing Genomics DNA Extraction Plasmodium falciparum Escherichia coli Chromatin Homologous recombination noncoding rna Telomere healing Mutually exclusive expression Multicopy gene families Subtelomeric domains

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