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)

The high rate of mutation which is inherent in reverse transcription of the HIV genome is a result of the lack of proof-reading function of the reverse transcriptase enzyme. This has allowed the HIV virus to develop resistance to multiple antiviral agents. It may be possible to use this viral property to advantage by treatment with an antiviral nucleoside analogue which is a close structural isostere of uridine and deoxyuridine. The drug is unable to form hydrogen bonds with adenine and will be excluded from host cell DNA by its 3' to 5' proof-reading exonuclease activity. However, reverse transcriptase, which has no such mechanism, will allow incorporation of the drug into proviral DNA. The drug will have an inhibitory effect on RNase H function. It will also be expected to cause delay in elongation at those sites in the template strand that contain two or more adjacent adenine bases, because two drug molecules will, for practical purposes, never be inserted in the same strand next to each other. The length of the delay in strand elongation will therefore be a function of the availability of the natural NTP or dNTP. Both the rate and fidelity of protein synthesis will be affected by the drug. There will be decreased stability of the proviral double stranded DNA and if the proviral DNA is able to integrate into the host cell chromosome, double stranded breaks may be produced by the host cells' DNA repair mechanisms. Finally there will be a specific 'strand trade' mutation that the drug will induce specifically into viral but not into cellular genetic material.
 ...
PMID:A nucleoside analogue of 2, 4-difluoropyridine has potential as an antiretroviral agent with multiple and unique mechanisms of action, and may be effective against the HIV organism. 1105 20

The P-boranophosphates are efficient and near perfect mimics of natural nucleic acids in permitting reading and writing of genetic information with high yield and accuracy. Substitution of a borane (-BH3) group for oxygen in the phosphate ester bond creates an isoelectronic and isosteric mimic of natural nucleotide phosphate esters found in mononucleotides, i.e., AMP and ATP, and in RNA and DNA polynucleotides. Compared to natural nucleic acids, the boranophosphate RNA and DNA analogs demonstrate increased lipophilicity and resistance to endo- and exonucleases, yet they retain negative charge and similar spatial geometry. Borane groups can readily be introduced into the NTP and dNTP nucleic acid monomer precursors to produce alpha-P-borano nucleoside triphosphate analogs (e.g., NTPalphaB and dNTPalphaB). The NTPalphaB and dNTPalphaB are, in fact, good to excellent substrates for RNA and DNA polymerases, respectively, and allow ready enzymatic synthesis of RNA and DNA with P-boranophosphate linkages. Further, boranophosphate polymer products are good templates for replication, transcription, and gene expression; boronated RNA products are also suitable for reverse transcription to cDNA. Fully substituted boranophosphate DNA can activate the RNase H cleavage of RNA in RNA:DNA hybrids. Moreover, certain dideoxy-NTPalphaB analogs appear to be better substrates for viral reverse transcriptases than the regular ddNTPs, and may offer promising prodrug alternatives in antiviral therapy. These properties make boranophosphates promising candidates for diagnostics; aptamer selection; gene therapy; and antiviral, antisense, and RNAi therapeutics. The boranophosphates constitute a versatile family of phosphate mimics for processing genetic information and modulating gene function.
 ...
PMID:Reading, writing, and modulating genetic information with boranophosphate mimics of nucleotides, DNA, and RNA. 1475 19