Abstract:
:Triantennary N-acetyl galactosamine (GalNAc, GN3: ), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisense oligonucleotides (ASOs) 6-10-fold in mouse liver. When combined with next-generation ASO designs comprised of short S-cEt (S-2'-O-Et-2',4'-bridged nucleic acid) gapmer ASOs, ∼ 60-fold enhancement in potency relative to the parent MOE (2'-O-methoxyethyl RNA) ASO was observed. GN3: -conjugated ASOs showed high affinity for mouse ASGPR, which results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells. After internalization into cells, the GN3: -ASO conjugate is metabolized to liberate the parent ASO in the liver. No metabolism of the GN3: -ASO conjugate was detected in plasma suggesting that GN3: acts as a hepatocyte targeting prodrug that is detached from the ASO by metabolism after internalization into the liver. GalNAc conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice. The unconjugated ASOs are currently in late stage clinical trials for the treatment of familial chylomicronemia and TTR-mediated polyneuropathy. The ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Prakash TP,Graham MJ,Yu J,Carty R,Low A,Chappell A,Schmidt K,Zhao C,Aghajan M,Murray HF,Riney S,Booten SL,Murray SF,Gaus H,Crosby J,Lima WF,Guo S,Monia BP,Swayze EE,Seth PPdoi
10.1093/nar/gku531subject
Has Abstractpub_date
2014-07-01 00:00:00pages
8796-807issue
13eissn
0305-1048issn
1362-4962pii
gku531journal_volume
42pub_type
杂志文章abstract::We report the latest release (version 3.0) of the CATH protein domain database (http://www.cathdb.info). There has been a 20% increase in the number of structural domains classified in CATH, up to 86 151 domains. Release 3.0 comprises 1110 fold groups and 2147 homologous superfamilies. To cope with the increases in di...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkl959
更新日期:2007-01-01 00:00:00
abstract::Mutator-like transposable elements (MULEs) are widespread across fungal, plant and animal species. Despite their abundance and importance as genetic tools in plants, the transposition mechanism of the MULE superfamily was previously unknown. Discovery of the Muta1 element from Aedes aegypti and its successful transpos...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkx357
更新日期:2017-06-20 00:00:00
abstract::An important problem in genomics is automatically clustering homologous proteins when only sequence information is available. Most methods for clustering proteins are local, and are based on simply thresholding a measure related to sequence distance. We first show how locality limits the performance of such methods by...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkj515
更新日期:2006-03-17 00:00:00
abstract::In small oocytes of Xenopus species, two sets of 5S RNA genes, oocyte-type and somatic-type, are fully activated. The 5S RNA transcripts are temporarily stored, half in association with TFIIIA to form a 7S particle, the other half in association with tRNA and two proteins (p48 and p43) to form a 42S particle. It has b...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/15.21.8679
更新日期:1987-11-11 00:00:00
abstract::Synthetic oligonucleotides were used to introduce mutations into the lacPUV5 promoter. Four mutations were obtained at positions -13, -14, and -15, with respect to the transcriptional start site. The effects of these mutations were measured in vivo and the results are discussed with respect to the consensus sequence a...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/12.9.4011
更新日期:1984-05-11 00:00:00
abstract::We have prepared several novel phosphoramidites and have synthesised oligonucleotides incorporating them internally. The presence of these residues in an oligonucleotide template presents an impossible barrier to primed synthesis by Taq DNA polymerase. When extended as polymerase chain reaction products, these oligonu...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/21.5.1155
更新日期:1993-03-11 00:00:00
abstract::SynergyFinder (https://synergyfinder.fimm.fi) is a stand-alone web-application for interactive analysis and visualization of drug combination screening data. Since its first release in 2017, SynergyFinder has become a widely used web-tool both for the discovery of novel synergistic drug combinations in pre-clinical mo...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkaa216
更新日期:2020-07-02 00:00:00
abstract::In many organisms (e.g., gram-positive eubacteria) Gin-tRNA is not formed by direct glutaminylation of tRNAGln but by a specific transamidation of Glu-tRNAGln. We wondered whether a similar transamidation pathway also operates in the formation of Asn-tRNA in these organisms. Therefore we tested in S-100 preparations o...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/24.14.2648
更新日期:1996-07-15 00:00:00
abstract::We describe PReMod, a new database of genome-wide cis-regulatory module (CRM) predictions for both the human and the mouse genomes. The prediction algorithm, described previously in Blanchette et al. (2006) Genome Res., 16, 656-668, exploits the fact that many known CRMs are made of clusters of phylogenetically conser...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkl879
更新日期:2007-01-01 00:00:00
abstract::The thyroid hormone receptor alpha (THRA or c-erbA-1) gene belongs to a family of genes which encode nuclear receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. These receptors are composed of several domains important for hormone-binding, DNA-binding, dimerizatio...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/19.5.1105
更新日期:1991-03-11 00:00:00
abstract::Sequencing of RNAs (RNA-Seq) has revolutionized the field of transcriptomics, but the reads obtained often contain errors. Read error correction can have a large impact on our ability to accurately assemble transcripts. This is especially true for de novo transcriptome analysis, where a reference genome is not availab...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkt215
更新日期:2013-05-01 00:00:00
abstract::The particular behaviour of eukaryotic RNA polymerases along different gene regions and amongst distinct gene functional groups is not totally understood. To cast light onto the alternative active or backtracking states of RNA polymerase II, we have quantitatively mapped active RNA polymerases at a high resolution fol...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gku1349
更新日期:2015-01-01 00:00:00
abstract::Restriction endonucleases are highly specific in recognizing the particular DNA sequence they act on. However, their activity is affected by sequence context, enzyme concentration and buffer composition. Changes in these factors may lead to either ineffective cleavage at the cognate restriction site or relaxed specifi...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkt257
更新日期:2013-06-01 00:00:00
abstract::Calf lens messenger fractions have been purified on poly(dT)-cellulose. The purified RNA's have been analyzed as nucleosides by a method which can be used on a micro-scale with highly reproduceble results. Both the 10S and 14S lens mRNA contain poly A sequences. The poly A content found in 14S mRNA cannot account for ...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/1.2.245
更新日期:1974-02-01 00:00:00
abstract::A set of new sulfurizing agents representing disulfides of arylsulfonic acids has been developed for the automated synthesis of phosphorothioate oligonucleotide analogues via the phosphoramidite method. These reagents, such as bis(benzenesulfonyl)disulfide, bis(p-toluenesulfonyl)disulfide, bis(p-methoxybenzensulfonyl)...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/23.20.4029
更新日期:1995-10-25 00:00:00
abstract::2'-O-(2-methoxyethyl) (2'-MOE) RNA possesses favorable pharmocokinetic properties that make it a promising option for the design of oligonucleotide drugs. Telomerase is a ribonucleoprotein that is up-regulated in many types of cancer, but its potential as a target for chemotherapy awaits the development of potent and ...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/29.8.1683
更新日期:2001-04-15 00:00:00
abstract::ATRX and MeCP2 belong to an expanding group of chromatin-associated proteins implicated in human neurodevelopmental disorders, although their gene-regulatory activities are not fully resolved. Loss of ATRX prevents full repression of an imprinted gene network in the postnatal brain and in this study we address the mec...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gku564
更新日期:2014-07-01 00:00:00
abstract::Interactions between proteins, drugs, water and B-DNA minor groove have been analyzed in crystal structures of 60 protein-DNA and 14 drug-DNA complexes. It was found that only purine N3, pyrimidine O2, guanine N2 and deoxyribose O4' are involved in the interactions, and that contacts to N3 and O2 are most frequent and...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/30.5.1182
更新日期:2002-03-01 00:00:00
abstract::The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activati...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkq861
更新日期:2011-03-01 00:00:00
abstract::The EcoCyc database (http://EcoCyc.org/) is a comprehensive source of information on the biology of the prototypical model organism Escherichia coli K12. The mission for EcoCyc is to contain both computable descriptions of, and detailed comments describing, all genes, proteins, pathways and molecular interactions in E...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gki108
更新日期:2005-01-01 00:00:00
abstract::The mode of action of regulated promoters is largely determined by kinetic parameters which govern the interaction between promoters and proteins involved in induction and repression of transcription. To gain insight into the interplay between positively and negatively acting transcriptional regulators, in this case A...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/29.18.3873
更新日期:2001-09-15 00:00:00
abstract::pS194 is a naturally occurring Staphylococcus aureus plasmid encoding streptomycin resistance. The plasmid has a copy number of about 25 per cell, and belongs to the inc5 incompatibility group. The nucleotide sequence of pS194 has been determined and consists of 4397 base pairs including four open reading frames poten...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/16.5.2179
更新日期:1988-03-25 00:00:00
abstract::Metagenomics has been employed to systematically sequence, classify, analyze and manipulate the entire genetic material isolated from environmental samples. Finding genes within metagenomic sequences remains a formidable challenge, and noncoding RNA genes other than those encoding rRNA and tRNA are not well annotated ...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkm057
更新日期:2007-01-01 00:00:00
abstract::Bacterial genomes encode a plethora of small RNAs (sRNAs), which are heterogeneous in size, structure and function. Most sRNAs act as post-transcriptional regulators by means of specific base pairing interactions with the 5'-untranslated region of mRNA transcripts, thereby modifying the stability of the target transcr...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkr467
更新日期:2011-07-01 00:00:00
abstract::Therapeutic small interfering RNAs (siRNAs) are composed of chemically modified nucleotides, which enhance RNA stability and increase affinity in Watson-Crick base pairing. However, the precise fate of such modified nucleotides once the siRNA is degraded within the cell is unknown. Previously, we demonstrated that deo...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkt120
更新日期:2013-04-01 00:00:00
abstract::Recombinase proteins assembled into helical filaments on DNA are believed to be the catalytic core of homologous recombination. The assembly, disassembly and dynamic rearrangements of this structure must drive the DNA strand exchange reactions of homologous recombination. The sensitivity of eukaryotic recombinase acti...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gki640
更新日期:2005-06-08 00:00:00
abstract::The effect of different levels of mercury substitution on the rate and extent of hybridisation of globin mRNA with a complementary DNA (cDNA) copy has been investigated. It was found that mercuration significantly reduces both the rate of hybridisation and the extent of the reaction, but that these effects are abolish...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/7.8.2357
更新日期:1979-12-20 00:00:00
abstract::The large terminase subunit is a central component of the genome packaging motor from tailed bacteriophages and herpes viruses. This two-domain enzyme has an N-terminal ATPase activity that fuels DNA translocation during packaging and a C-terminal nuclease activity required for initiation and termination of the packag...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gks974
更新日期:2013-01-07 00:00:00
abstract::The DNA topoisomerase from Agrobacterium tumefaciens has been purified to apparent homogeneity. The enzyme is a single polypeptide of about 100,000 in molecular weight. No apparent separation of the nicking and sealing activities could be obtained in attempts to separate the two activities by a variety of methods, inc...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/9.4.909
更新日期:1981-02-25 00:00:00
abstract::A microchip method has been developed for massive and parallel thermodynamic analyses of DNA duplexes. Fluorescently labeled oligonucleotides were hybridized with oligonucleotides immobilized in the 100 x 100 x 20 mum gel pads of the microchips. The equilibrium melting curves for all microchip duplexes were measured i...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/26.6.1515
更新日期:1998-03-15 00:00:00