Abstract:
:Preliminary investigations of the physical properties of oligonucleotide analogs that contain alternating methylphosphonate/phosphodiester linkages are described. An alternating oligo-2'-O-methylribonucleoside methylphosphonate, oligomer 1676, whose sequence is complementary to the upper hairpin region of human immunodeficiency virus TAR RNA, has been synthesized. This 15-mer forms a very stable duplex with its complementary RNA target, whose melting temperature is 71 degrees C. Introduction of two mismatched bases reduces the melting temperature by 16 degrees C. Similar results were obtained with the all-phosphodiester version of oligomer 1676, which demonstrates that introduction of the methylphosphonate linkages does not significantly perturb the ability of the oligo-2'-O-methylribonucleoside methylphosphonate to bind to RNA. Unlike the phosphodiester oligomer, however, oligomer 1676 is completely resistant to hydrolysis by the 3'-exonuclease activity found in mammalian serum. The interactions between nuclease-resistant, 5'-psoralen-derivatized, alternating oligo-2'-deoxypyrimidine methylphosphonates and double-stranded DNA were also studied. A 15-mer that contains thymine, 5-methylcytosine, and 5-propynyl-uracil forms a triplex with a polypurine tract found in the env gene of human immunodeficiency virus proviral DNA with an apparent dissociation constant of 400 nM at 22 degrees C. Maximal triplex formation by these oligomers is observed at approximately 2.5 mM magnesium, whereas maximal triplex formation by the corresponding all-phosphodiester oligomers occurs between 10 and 20 mM magnesium. This reduced magnesium dependence most likely results from reduced charge repulsion between the backbones of the methylphosphonate oligomer and purine strand of the target. The nuclease stability and ability of the methylphosphonate oligomers to form stable complexes with their target nucleic acids suggest that these oligomers are potential candidates for use as antisense or antigene agents in cell culture.
journal_name
Pharmacol Therjournal_title
Pharmacology & therapeuticsauthors
Miller PS,Cassidy RA,Hamma T,Kondo NSdoi
10.1016/s0163-7258(99)00054-6subject
Has Abstractpub_date
2000-03-01 00:00:00pages
159-63issue
3eissn
0163-7258issn
1879-016Xpii
S0163725899000546journal_volume
85pub_type
杂志文章,评审abstract::In the past 4 years, RNA interference (RNAi) has become widely used as an experimental tool to analyse the function of mammalian genes, both in vitro and in vivo. By harnessing an evolutionary conserved endogenous biological pathway, first identified in plants and lower organisms, double-stranded RNA (dsRNA) reagents ...
journal_title:Pharmacology & therapeutics
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abstract::A number of neuronal functions, including synaptic plasticity, depend on proper regulation of synaptic proteins, many of which can be rapidly regulated by phosphorylation. Neuronal activity controls the function of these synaptic proteins by exquisitely regulating the balance of various protein kinase and protein phos...
journal_title:Pharmacology & therapeutics
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abstract::Natriuretic peptides play a critical role in coordination of fluid/electrolyte balance and vascular tone. The renal effects of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are distinct from the paracrine effects of vascular C-type natriuretic peptide (CNP). CNP is widely expressed t...
journal_title:Pharmacology & therapeutics
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abstract::This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin and accompanying loss of frataxin protein. Frataxin insuf...
journal_title:Pharmacology & therapeutics
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abstract::Destruction of the established tumour vasculature by a class of compound termed Vascular Disrupting Agents (VDAs) is showing considerable promise as a viable approach for the management of solid tumours. VDAs induce a rapid shutdown and collapse of tumour blood vessels, leading to ischaemia and consequent necrosis of ...
journal_title:Pharmacology & therapeutics
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abstract::In the search for new approaches to cancer therapy, the first alkyllysophospholipid (ALP) analogs were designed and studied about two decades ago, either as potential immunomodulators or as antimetabolites of phospholipid metabolism. In the meantime, it has been demonstrated that they really act in this way. However, ...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
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journal_title:Pharmacology & therapeutics
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journal_title:Pharmacology & therapeutics
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journal_title:Pharmacology & therapeutics
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journal_title:Pharmacology & therapeutics
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journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
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更新日期:2000-01-01 00:00:00
abstract::Methamphetamine (METH) abuse is a major public health issue around the world, yet there are currently no effective pharmacotherapies for the treatment of METH addiction. METH is a potent psychostimulant that increases extracellular dopamine levels by targeting the dopamine transporter (DAT) and alters neuronal activit...
journal_title:Pharmacology & therapeutics
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journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
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更新日期:1991-01-01 00:00:00
abstract::Neutrophils form an essential part of innate immunity against infection. Cancer chemotherapy-induced neutropenia (CCIN) is a condition in which the number of neutrophils in a patient's bloodstream is decreased, leading to increased susceptibility to infection. Granulocyte colony-stimulating factor (GCSF) has been the ...
journal_title:Pharmacology & therapeutics
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journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.pharmthera.2004.02.003
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abstract::The demonstration that RNA can be cleaved by cis or trans ribozymes (catalytic RNAs, RNA enzymes) has potentially important therapeutic implications. Since their discovery in the 1980s, the biochemistry and conserved sequences of ribozymes have been well characterized. Ribozymes are effective modulators of gene expres...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
doi:10.1016/0163-7258(95)02008-x
更新日期:1995-01-01 00:00:00
abstract::A majority of angiogenic factors has been shown to be produced by macrophages. This review will give a concise description of their biochemical nature, their isolation from macrophages and their angiogenic activity. Among the factors with mitogenic effects on endothelial cells are basic fibroblast growth factor (bFGF)...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
doi:10.1016/0163-7258(91)90077-y
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journal_title:Pharmacology & therapeutics
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doi:10.1016/j.pharmthera.2010.09.005
更新日期:2011-02-01 00:00:00
abstract::Since its commercial advent in 1985, transcranial magnetic stimulation (TMS), a technique for stimulating neurons in the cerebral cortex through the scalp, safely and with minimal discomfort, has captured the imaginations of scientists, clinicians and lay observers. Initially a laboratory tool for neurophysiologists s...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.pharmthera.2011.09.003
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abstract::Cardiovascular disease (CVD) continues to be a leading cause of death worldwide with atherosclerosis being the major underlying pathology. The interplay between lipids and immune cells is believed to be a driving force in the chronic inflammation of the arterial wall during atherogenesis. Atherosclerosis is initiated ...
journal_title:Pharmacology & therapeutics
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doi:10.1016/j.pharmthera.2018.08.012
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journal_title:Pharmacology & therapeutics
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abstract::Progranulin (PGRN) is abundantly expressed in epithelial cells, immune cells, neurons, and chondrocytes, and reportedly contributes to tumorigenesis. PGRN is a crucial mediator of wound healing and tissue repair. PGRN also functions as a neurotrophic factor and mutations in the PGRN gene resulting in partial loss of t...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
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abstract::Enzymes of the UDP-glucuronosyltransferase (UGT) superfamily contribute to the elimination of drugs from almost all therapeutic classes. Awareness of the importance of glucuronidation as a drug clearance mechanism along with increased knowledge of the enzymology of drug and chemical metabolism has stimulated interest ...
journal_title:Pharmacology & therapeutics
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abstract::In recent years there has been an explosion of interest in how genes regulate alcohol drinking and contribute to alcoholism. This work has been stimulated by the completion of the human and mouse genome projects and the resulting availability of gene microarrays. Most of this work has been performed in drinking animal...
journal_title:Pharmacology & therapeutics
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abstract::The pulmonary endothelium plays a crucial role in lung development and function during the perinatal period. Its 2 most important functions at this time are to help reduce pulmonary vascular resistance (PVR) in order to permit the entire cardiac output to pass through the lungs for the first time and to facilitate the...
journal_title:Pharmacology & therapeutics
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abstract::Protein kinases recognize and bind to specific amino acid sequences on their protein substrates. These sequences can be readily identified using combinatorial peptide libraries. Unfortunately, conventional peptide libraries are not designed to identify subtle structural factors that can dramatically enhance enzyme aff...
journal_title:Pharmacology & therapeutics
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更新日期:2002-02-01 00:00:00
abstract::The use of Translocator Protein 18 kDa (TSPO) as a clinical neuroimaging biomarker of brain injury and neuroinflammation has increased exponentially in the last decade. There has been a furious pace in the development of new radiotracers for TSPO positron emission tomography (PET) imaging and its use has now been exte...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.pharmthera.2018.09.003
更新日期:2019-02-01 00:00:00
abstract::In addition to their prominent roles in the control of reproduction, estrogens are important modulators of energy balance, as evident in conditions of deficiency of estrogens, which are characterized by increased feeding and decreased energy expenditure, leading to obesity. AMP-activated protein kinase (AMPK) is a ubi...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.pharmthera.2017.03.014
更新日期:2017-10-01 00:00:00
abstract::AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor trafficking is a fundamental mechanism for regulating synaptic strength, and hence may underlie cellular processes involved in learning and memory. PICK1 (protein interacting with C-kinase) is a PDZ and BAR domain-containing protein that has rece...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.pharmthera.2008.02.002
更新日期:2008-04-01 00:00:00
abstract::Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) was initially identified as the major receptor for oxidized LDL (OxLDL) in endothelial cells. Its inducible expression in macrophages and smooth muscle cell was also observed. LOX-1 is a Type II membrane protein with a typical C-type lectin structur...
journal_title:Pharmacology & therapeutics
pub_type: 杂志文章,评审
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更新日期:2002-07-01 00:00:00