Theoretical studies of the conformational properties of ribavirin.

Miles, Douglas L.; Miles, Daniel W.; Redington, Patrick; Eyring, Henry

doi:10.1073/pnas.73.12.4257

Cited by 15 publications

(12 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This comparison indicated that 3-NPN and ribavirin are practically identical in overall structure in the solid state, while differing substantially in hydrogen bonding ability. Interestingly, solution phase studies with ribavirin have revealed a preference for the syn conformation of the heterocyclic base ( , ). On the basis of the substantial structural similarities, the observed differences in biological activity are presumably not a result of conformational effects.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Antiviral Evaluation of a Mutagenic and Non-Hydrogen Bonding Ribonucleoside Analogue: 1-β-d-Ribofuranosyl-3-nitropyrrole

et al. 2002

View full text Add to dashboard Cite

Synthetic small molecules that promote viral mutagenesis represent a promising new class of antiviral therapeutics. Ribavirin is a broad-spectrum antiviral nucleoside whose antiviral mechanism against RNA viruses likely reflects the ability of this compound to introduce mutations into the viral genome. The mutagenicity of ribavirin results from the incorporation of ribavirin triphosphate opposite both cytidine and uridine in viral RNA. In an effort to identify compounds with mutagenicity greater than that of ribavirin, we synthesized 1-beta-D-ribofuranosyl-3-nitropyrrole (3-NPN) and the corresponding triphosphate (3-NPNTP). These compounds constitute RNA analogues of the known DNA nucleoside 1-(2'-deoxy-beta-D-ribofuranosyl)-3-nitropyrrole. The 3-nitropyrrole pseudobase has been shown to maintain the integrity of DNA duplexes when placed opposite any of the four nucleobases without requiring hydrogen bonding. X-ray crystallography revealed that 3-NPN is structurally similar to ribavirin, and both compounds are substrates for adenosine kinase, an enzyme critical for conversion to the corresponding triphosphate in cells. Whereas ribavirin exhibits antiviral activity against poliovirus in cell culture, 3-NPN lacks this activity. Evaluation of 3-NPNTP utilization by poliovirus RNA-dependent RNA polymerase (RdRP) revealed that 3-NPNTP was not accepted universally. Rather, incorporation was only observed opposite A and U in the template and at a rate 100-fold slower than the rate of incorporation of ribavirin triphosphate. This diminished rate of incorporation into viral RNA likely precludes 3-NPN from functioning as an antiviral agent. These results indicate that hydrogen bonding substituents are critical for efficient incorporation of ribonucleotides into RNA by viral RdRPs, thus providing important considerations for the design of improved mutagenic antiviral nucleosides.

show abstract

Section: Discussionmentioning

confidence: 99%

Synthesis and Antiviral Evaluation of a Mutagenic and Non-Hydrogen Bonding Ribonucleoside Analogue: 1-β-d-Ribofuranosyl-3-nitropyrrole

et al. 2002

View full text Add to dashboard Cite

show abstract

“…8) with those obtained for purine nucleosides (see refs. 8,19,20). Overall, the benzimidazole nucleosides show narrower and deeper depressions in the syn and anti regions than is generally found for the purine nucleosides.…”

mentioning

confidence: 90%

“…The iterative extended Huckel theory used recently in our studies of nucleoside conformation (8,19,20) gives the conformational profiles exhibited in Fig. 4.…”

mentioning

confidence: 99%

Conformation of nucleosides: circular dichroism study on the syn-anti conformational equilibrium of 2-substituted benzimidazole nucleosides.

Miles¹,

Townsend²,

Miles³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The solution conformations of 2-substituted derivatives of l(B-D-ribofuranosyl)benzimidazole have been determined by circular dichroism spectroscopy in aqueous solutions. It is shown that analogs with methyl, amino, or methylamino substituents at position 2 of the benzimidazole ring (position 8 of the purine ring) have predominantly anti conformations, whereas analogs with chloro, aza, methoxy, or methylmercapto substituents have predominantly syn conformations.The preferred solution conformations of the benzimidazole nucleosides and analogous purine nucleosides are compared.The results demonstrate that the replacement of nitrogen by carbon at position 3 of the purine ring of purine (,B) nucleosides leads to important conformational consequences, which are strengthened or neutralized by substituents at position 8 of the purine ring.In this paper the syn-anti glycosidic conformational equilibrium of 2-substituted derivatives of l-(f3-D-ribofuranosyl)-benzimidazole is related to the circular dichroism (CD) spectra. The analysis is facilitated by studies on reference benzimidazole nucleosides that are unequivocally constrained to the syn conformation by bulky substituents and to the anti conformation by covalent bonding. Calculations of glycosidic conformational energy are also included. It is found that analogs with methyl, amino, and methylamino substituents at position 2 have predominantly anti conformations in aqueous solution, whereas analogs with chloro, aza, methoxy, or methylmercapto substituents have predominantly syn populations. Because the 2-substituent of a benzimidazole nucleoside may be considered analogous to the 8-substituent of a purine nucleoside, our work may provide insights into the pivotal conformational factors that regulate the glycosidic conformation of biologically important purine nucleosides. Considerable attention has been devoted towards understanding these factors, because the biological activities of some purine nucleoside and nucleotide substrates are mediated by their glycosidic conformational preferences (1-9). In a recent article (8), we presented evidence that replacement of N3 of the purine ring by CH produced important conformational effects, which are now shown to be strengthened or neutralized by substituents at position 8 of the purine ring. The preference for the anti conformation engendered by 2-amino and 2-methylamino is apparently realized in purine nucleosides as well according to a recent NMR study (7). Our CD results for the 2-methylbenzimidazole nucleoside derivative indicate that the anti conformation is produced by the methyl substituent. The chemical shift changes for 8-methyladenosine indicate that the syn conformation is produced by the analogous methyl substituent (6) on the adenine ring. EXPERIMENTAL CD measurements were made with the Cary 60 spectropolarimeter at very low scan speeds when necessary. In general, the signal-to-noise ratio obtained on benzimidazole nucleosides are several times more favorable than those obtained on purine nucleosides. ...

show abstract

“…Calculations that we have done with other crystal forms of adenosine indicate that the conformational energy profile obtained by theoretical calculations on a rigid molecule are modified by the starting coordinates or crystal structure chosen for the calculation. A dramatic example of this has been illustrated by calculations on the two crystal forms of ribavirin (47,48). In general, the high anti conformation in adenosine can be considered as being slightly higher in energy than the anti conformation for most of the probable arrangements of atomic coordinates.…”

mentioning

confidence: 99%

Conformational basis for the activation of adenylate cyclase by adenosine

Miles

Eyring

1977

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The ability of adenosine to stimulate adenylate cyclase IATP pyrophosphate-lyase (cyclizing), EC 4.6.1.11 and increase adenosine 3':5'-cyclic monophosphate (cAMP) levels has important biochemical consequences. These include the suppression of immune responses and cardiovascular effects. Recent investigations involving the ability of adenosine and adenosine analogs to stimulate adenylate cyclase provided experimental data that appear to be correlated with the ability of adenosine and analogs of adenosine to exist in the glycosidic high anti conformation. There are several aspects to the toxicity associated with an excess of adenosine (1-11). The enzymes adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) and adenosine kinase (ATP:adenosine-5'-phosphotransferase, EC 2.7.1.20) compete for adenosine. At higher concentrations of adenosine, adenosine deaminase dominates (11)(12)(13)(14) and protects the body from the effects of an excess of adenosine. One of these effects is the suppression of immune responses associated with the activation by adenosine of adenylate cyclase ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.11 which increases cAMP levels (15, 16). Adenosine stimulation of adenosine 3':5'-cyclic monophosphate (cAMP) production is attributed to the interaction of adenosine with a receptor for adenosine on the external cell surface (15,(17)(18)(19)(20)(21)(22)(23)(24). Immunodeficiency diseases have been associated with the loss of adenosine deaminase activity (5, 25-32).The coronary vasodilator activity of adenosine has recently been reviewed (33,34). The cardiovascular effects of adenosine are potentiated by inhibitors of either adenosine deaminase or the uptake of adenosine by the heart (35-42), both of which increase extracellular adenosine concentrations which stimulates adenylate cyclase.Factors, such as the loss of adenosine deaminase activity, that increase adenosine levels result in increased cAMP levels which are responsible for the immunosuppressive (5, 15) and cardiovascular (33-42) effects of adenosine. In both situations the action of adenosine at a receptor on the external cell surface (15, 17-24) appears to require that adenosine be oriented in the glvcosidic high anti conformation. This conclusion is suggested by the correlation between the conformational properties of adenosine and adenosine analogs and their capacities to stimulate adenylate cyclase. CALCULATIONS In order to calculate the conformational differences among adenosine, 2'-deoxyadenosine, and 9-1-D-arabinofuranosyladenine (Ara-adenine) we used the iterative extended Huckel theory (IEHT) method (43). The starting coordinates for the calculations were taken from the crystal structures of these molecules (44-46). The conformational definitions that we will use are shown in Fig. 1. The high anti conformation corresponds to dihedral angles between 750 and 1650. Fig. 2 shows the variation in total energy of adenosine with rotation about the glycosidic (C1'-N9) bond. The entire high anti conformation range is energetical...

show abstract

Theoretical studies of the conformational properties of ribavirin.

Cited by 15 publications

References 27 publications

Synthesis and Antiviral Evaluation of a Mutagenic and Non-Hydrogen Bonding Ribonucleoside Analogue: 1-β-d-Ribofuranosyl-3-nitropyrrole

Synthesis and Antiviral Evaluation of a Mutagenic and Non-Hydrogen Bonding Ribonucleoside Analogue: 1-β-d-Ribofuranosyl-3-nitropyrrole

Conformation of nucleosides: circular dichroism study on the syn-anti conformational equilibrium of 2-substituted benzimidazole nucleosides.

Conformational basis for the activation of adenylate cyclase by adenosine

Contact Info

Product

Resources

About