Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.4 (RNase H)
 2,751 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uniformly modified nucleic acids analogues, oligonucleotide N3'-->P5' phosphoramidates, containing 3'-amino instead of 3'-hydroxyl nucleosides, were synthesized and studied. These compounds form very stable duplexes with complementary native phosphodiester DNA and exceptionally stable duplexes with RNA strands. Increases in duplex melting temperature, deltaTm, relatively to their phosphodiester counterparts, reaches 2.9-3.5 degrees C per modified nucleoside. Moreover, the phosphoramidate compounds form extremely stable triple stranded complexes with single or double stranded DNA oligomers under near physiological salt and pH conditions. Melting temperatures of these triplexes usually exceed that of the isosequential phosphodiester counterparts by up to 35 degrees C. For 11-15-mers 2'-deoxyphosphoramidates are structurally and functionally similar to the native RNA molecules and thus can be used as RNA decoys. They are resistant to enzymatic digestion by nucleases both in vitro and in vivo. Oligonucleotide phosphoramidates apparently are cell permeable, and they have a good bioavailability and biodistribution, while being non-toxic in mice at therapeutically relevant doses. Duplexes of the several studied phosphoramidates with complementary RNA strands apparently are not substrates for RNase H in vitro. Despite that, these compounds exerted high sequence-specific antisense activity in various cell lines and in SCID mice. The observed in vitro lack of RNase H recognition of the RNA:phosphoramidate duplexes may result in better specificity in biological activity of these compounds relative to RNase H inducing oligonucleotides. Experimental results also indicate that oligonucleotide phosphoramidates can be used as efficient and specific modulators of gene expression by an antigene mechanism of action. Finally, the oligo-2'-deoxyphosphoramidate double stranded complexes can structurally mimic native RNA complexes, which could be efficiently and specifically recognized by the RNA binding proteins, such as HIV-1 Rev and Tat.
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PMID:Oligonucleotide N3'-->P5' phosphoramidates as potential therapeutic agents. 1080 3

Sexual transmission of HIV is the major cause of spread of HIV in Africa and the Third World and is an unmet medical need. Recently, microbicides have attracted attention because they allow females to protect themselves and their offspring. We are exploiting one of the four retroviral enzymes, the ribonuclease H, RNase H, as a novel approach for a microbicide. It is the only enzyme of HIV not yet targeted by antiretroviral therapy. The enzyme is linked to the reverse transcriptase (RT) and hydrolyzes the RNA moiety of RNA-DNA hybrids. The RNase H is located inside virus particles and normally functions during viral replication inside cells. Here we show that activating the RNase H prematurely inside the virus particles destroys the viral genome and abrogates viral infectivity. The antiviral compound consists of a synthetic oligodeoxynucleotide (ODN), which creates an artificial RNA-DNA hybrid substrate for the RNase H inside the particle. The compound was analyzed in mouse models including humanized SCID mice and the vagina of mice. Infection was reduced up to 1000-fold or could be completely prevented. The compound is suitable as microbicide or to prevent mother-to-child transmission.
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PMID:Premature activation of the HIV RNase H drives the virus into suicide: a novel microbicide? 2293 Nov 14