Nucleoside conformations

Blandin, Michel; Tran-Dinh, S.; Catlin, Joseph C.; Guschlbauer, Wilhelm

doi:10.1016/0005-2787(74)90368-2

Cited by 45 publications

(7 citation statements)

References 30 publications

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“…1-the conformation of the sugar moiety. As shown by studies on mono-and polymers ( 1,2,(18)(19)(20)(21)(22)(23)(24), it probably possesses a ribolike conformation but the low affinity of enzyme for its pseudo-substrate may be due to conformational enhancement: 2'-deoxy-2'-fluoronucleosides show a higher degree of 3' endo conformation than ribosides (1,2,23). That RNA synthesis was oreatly improved by replacing MgCI2 by MnCI2 may be correlated with the incorporation of deoxyribo-triphosphates into RNA by RNA Dolymerase in the presence of this same divalent cation (4).…”

Section: Discussionmentioning

confidence: 91%

2′-Deoxy-2′-fluorouridine-5′-triphosphates: a possible substrate for E. coli RNA polymerase

Vc¹,

Sarocchi-Landousy²,

Guschlbauer³

1979

Nucl Acids Res

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Section: Discussionmentioning

confidence: 91%

2′-Deoxy-2′-fluorouridine-5′-triphosphates: a possible substrate for E. coli RNA polymerase

Vc¹,

Sarocchi-Landousy²,

Guschlbauer³

1979

Nucl Acids Res

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“…Interestingly, PSI-6130 showed high selectivity against the closely related positive strand RNA virus bovine viral diarrhea virus, whereas the 2Ј-␣-hydroxy analog 2Ј-C-methylcytidine (NM107) inhibited both HCV and bovine viral diarrhea virus replication in cell culture (38). Fluoro-nucleosides may therefore provide considerable hydrogen bond acceptor functionality in the RNA polymerase active site (34), although such substitutions may also function by facilitating the formation of an RNA-like 3Ј-endo conformation in the RNA polymerase active site (39) or by accelerating the chemical reaction through electronic stabilization of the nucleophilic substitution reaction in the polymerase active site (40). Consistent with the conformational effect of the 2Ј-␣-fluoro substituent, PSI-6130 crystallized in the RNA typical 3Ј-endo conformation (38) similar to NM107 (Fig.…”

Section: Discussionmentioning

confidence: 99%

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

Klumpp

Kalayanov

et al. 2008

Journal of Biological Chemistry

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RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2-␣-hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of ␣-hydroxy moieties. 2-Deoxy-2-␤-fluoro-4-azidocytidine (RO-0622) and 2-deoxy-2-␤-hydroxy-4-azidocytidine (RO-9187) were excellent substrates for deoxycytidine kinase and were phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. As compared with previous reports on ribonucleosides, higher levels of triphosphate were formed from RO-9187 in primary human hepatocytes, and both compounds were potent inhibitors of HCV virus replication in the replicon system (IC 50 ‫؍‬ 171 ؎ 12 nM and 24 ؎ 3 nM for RO-9187 and RO-0622, respectively; CC 50 >1 mM for both). Both compounds inhibited RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4-azidocytidine) or 2-C-methyl nucleosides. Pharmacokinetic studies with RO-9187 in rats and dogs showed that plasma concentrations exceeding HCV replicon IC 50 values 8 -150-fold could be achieved by low dose (10 mg/kg) oral administration. Therefore, 2-␣-deoxy-4-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection. Hepatitis C virus (HCV)3 infection is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation. Current treatment options available to HCV-infected persons have limitations with regard to efficacy and tolerability. Only about 50% of individuals infected with HCV genotype 1 achieve sustained virological response when treated with a combination of pegylated interferon ␣ and ribavirin (1, 2). In addition, high viral load, age, body weight, co-infection with human immunodeficiency virus, and cirrhosis negatively affect the probability of achieving sustained virological response (3, 4). Therefore, there is an urgent need to develop new and more effective therapies for the treatment of HCV infection. A number of new antiviral candidates are currently being evaluated in clinical studies, the majority targeting either the HCV protease or HCV polymerase enzymes, which are essential for viral replication (5). The HCV RNA-dependent RNA polymerase, NS5B, contains the active site responsible for viral RNA synthesis and functions as part of a membrane-associated replicase complex. Nucleoside and non-nucleoside inhibitors of HCV polymerase h...

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“…Backgrounds were measured both at the beginning and end of each scan for lOsec. Three standard reflexions (060, (2) 217( 7) 1529 (3) 393 (10) 1666 (2) 704( 8) 1672 (3) 1436(11) 2031 (2) 1043( 7) 1772 (4) (13) 2835 (17) 3046 (26) 2917 (17) 2581 (18) 2474 (18) 2595 (20) 2500 (17) 2153 (15) 2093 (17) 2390 (14) 2337 (21) 4237 (13) 991 (17) 167 (12) 2420 (20) 1627 (15) 4159 (21) 6059 (25) 6606 (18) 287 (20) 325 (17) 168 (16) 186 (22) 1 (16) 271 (24) 169 (24) 409 (20) 605 (17) 698 (31) 768 (22) 8250 (21) 1372 (18) 890 (19) 678 (18) 230 (21) 45 (20) …”

Section: Nucleic Acids Researchmentioning

confidence: 99%

The crystal and molecular structure of 2′:-deoxy-2′:-fluoroinosine monohydrate

Hakoshima¹,

Omori²,

Tomita³

et al. 1981

Nucl Acids Res

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The structure of the hydrate of 2'-deoxy-2'-fluoroinosine has been determined by single-crystal x-ray diffraction. The nucleoside crystallizes in space group P2 12 121 with unit cell dimensions, a = 33.291, b = 10. 871, c = 6.897A. There are two nucleosides and two water molecules in the asymmetric unit. The structure was solved by direct methods and refined to a residual R = 0.095. The two independent nucleosides in the asymmetric unit show different conformations about the glycosidic bond, while other structural details are similar.

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Nucleoside conformations

Cited by 45 publications

References 30 publications

2′-Deoxy-2′-fluorouridine-5′-triphosphates: a possible substrate for E. coli RNA polymerase

2′-Deoxy-2′-fluorouridine-5′-triphosphates: a possible substrate for E. coli RNA polymerase

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

The crystal and molecular structure of 2′:-deoxy-2′:-fluoroinosine monohydrate

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