862179-59-7Relevant articles and documents
Inhibition of hepatitis C viral RNA-dependent RNA polymerase by α-P-boranophosphate nucleotides: Exploring apotential strategy for mechanism-based HCV drug design
Cheek, Marcus Adrian,Sharaf, Mariam L.,Dobrikov, Mikhail I.,Shaw, Barbara Ramsay
, p. 144 - 152 (2013)
Improved treatments for chronic HCV infections remain a challenge,and new chemical strategies are needed to expand the current paradigm. The HCV RNA polymerase (RdRP) has been a target for antiviral development. For the first time we show that the boranophosphate (BP)modification increases the sub-strate efficiency of ATP analogs into HCV NS5B Δ55 RdRP-catalyzed RNA. Boranophosphate nucleotides contain a borane (BH3) group substituted for anon-bridging phosphoryl oxygen of a normal phosphate group, resulting in a class of modified isoelectronic DNA and RNA mimics capable of modulating the reading and writing of genetic information. We determine that HCV NS5B Δ55, being a stereo specific enzyme, incorporates the Rp isomer of both ATP αB and the two boranophos phate analogs:2'-O-methyladenosine5'-(α-P-borano) triphosp hate (2'-OMe ATP αB, 5a) and 3'-deoxyadenosine 5'-(α-P-borano) triphosphate(3'-dATPaB, 5b). The Rp3 diastereomer of ATP αB (6), having noribose modifications, was found to be a slightly better substrate than natural ATP, showing a42%decrease inthe apparent Michaelis-Mentenconstan t (Km). The IC50 of both 2'-O-Me and 3'-deoxy ATP was decreased with the boranophosphate modification upto16-fold. This ''borano effect''was further confirmed by determining the steady-state in hibitory constant (Ki), showing a comparable potency shift (21-fold). These experiments also indicate that the boranophosphat eanalogs 5a and 5b inhibit HCV NS5B through a competitiv emode of inhibition. This evidence, together with previous crystal structure data, further supports the idea that HCV NS5B (in a similar manner toHIV-1 RT)discriminates against the 3'-deoxy modification via lost interactions between the 3'-OH on the ribose and the active site residues, or lost intramolecular hydrogen bonding interactions between the 3'-OH and the pyrophosphate leaving group during phosphoryl transfer. To our knowledge, these data represent the first time a phosphate modified NTP has been studied as a sub-strate for HCV NS5B RdRP.
ADENOSINE ANALOG AND ITS USE IN REGULATING THE CIRCADIAN CLOCK
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Paragraph 0160; 0161; 0162, (2018/08/12)
Provided are a kind of nucleoside analogue compounds, and compositions comprising these compounds and pentostatin, their use for modulating circadian rhythm, preferably, for shifting circadian phase, and methods for modulating circadian rhythm, preferably, for shifting circadian phase via these compounds or the compositions.
Nucleic acid related compounds. 101. S-adenosyl-L-homocysteine hydrolase does not hydrate (5'-fluoro)vinyl or (6'-halo)homovinyl analogues derived from 3'-deoxyadenosine or 3'-(chloro or fluoro)-3'-deoxyadenosine
Robins,Neschadimenko,Ro,Yuan,Borchardt,Wnuk
, p. 1205 - 1211 (2007/10/03)
S-Adenosyl-L-homocysteine (AdoHcy) hydrolase is crucial for the maintenance of biomethylation. The usual mechanistic sequence involves oxidation of AdoHcy at C3' followed by elimination of L-homocysteine, Michael addition of water, and reduction to give adenosine. A 6'- fluorohomovinyladenosine analogue (EDDFHA) undergoes hydration of the 5',6' double bond (hydrolytic activity) at a more rapid rate than oxidation at C3'. Three 4',5'-didehydro-5'-deoxy-5'-fluoro nucleoside analogues were prepared from 3'-deoxy- and 3'-(chloro and flouro)-3'-deoxyadenosine via generation of the vinyl fluorides by thermolysis of 5'-fluoro-5'-thioether sulfoxides. The 3'-deoxy analogues of 6'-halohomovinyladenosines were prepared by Wittig extension with a 3'-deoxy-5'-carboxaldehyde and halodestannylation of vinyl stannanes. The 3'-hydroxyl group appears to be essential for binding to AdoHcy hydrolase. No hydrolytic activity at C5', or C6' was observed with the nonoxidizable 3'-deoxy or 3'-(chloro or fluoro) analogues in contrast with their 3'-hydroxy counterparts (ZDDFA and EDDFHA). These 3'-modified analogues cannot reduce enzyme-bound NAD+ to NADH and do not produce time-dependent inhibition for AdoHcy hydrolase, but are weak competitive inhibitors (K(i) = 150-200 μM).
