189887-75-0Relevant academic research and scientific papers
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 (2013/08/23)
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.
Anticancer and antiviral effects and inactivation of S-adenosyl-L- homocysteine hydrolase with 5'-carboxaldehydes and oximes synthesized from adenosine and sugar-modified analogues
Wnuk, Stanislaw F.,Yuan, Chong-Sheng,Borchardt, Ronald T.,Balzarini, Jan,De Clercq, Erik,Robins, Morris J.
, p. 1608 - 1618 (2007/10/03)
Selectively protected adenine nucleosides were converted into 5'- carboxaldehyde analogues by Moffatt oxidation (dimethyl sulfoxide/dicyclohexylcarbodiimide/dichloroacetic acid) or with the Dess- Martin periodinane reagent. Hydrolysis of a 5'-fluoro-5'-S-methyl-5'-thio (α-fluoro thioether) arabinosyl derivative also gave the 5'-carboxaldehyde. Treatment of 5'-carboxaldehydes with hydroxylamine [or O-(methyl, ethyl, and benzyl)hydroxylamine] hydrochloride gave E/Z oximes. Treatment of purified oximes with aqueous trifluoroacetic acid and acetone effected trans-oximation to provide clean samples of 5'-carboxaldehydes. Adenosine (Ado)-5'- carboxaldehyde and its 4'-epimer are potent inhibitors of S-adenosyl-L- homocysteine (AdoHcy) hydrolase. They bind efficiently to the enzyme and undergo oxidation at C3' to give 3'-keto analogues with concomitant reduction of the NAD+ cofactor to give an inactive, tightly bound NADH-enzyme complex (type I cofactor-depletion inhibition). Potent type I inhibition was observed with 5'-carboxaldehydes that contain a ribo cis-2',3'-glycol. Their oxime derivatives are 'proinhibitors' that undergo enzyme-catalyzed hydrolysis to release the inhibitors at the active site. The 2'-deoxy and 2'-epimeric (arabinosyl) analogues were much weaker inhibitors, and the 3'-deoxy compounds bind very weakly. Ado-5'-carboxaldehyde oxime had potent cytotoxicity in tumor cell lines and was toxic to normal human cells. Analogues had weaker cytotoxic and antiviral potencies, and the 3'-deoxy compounds were essentially devoid of cytotoxic and antiviral activity.
