Design of Anti-HIV Compounds from Nucleoside to Nucleoside 5-Triphosphate Analogs. Problems and Perspectives

Kukhanova, Marina K.; Krayevsky, Alexander A.; Prusoff, William H.; Cheng, Yung-Chi

doi:10.2174/1381612003400687

Cited by 52 publications

(26 citation statements)

References 54 publications

(82 reference statements)

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“…Most nucleoside prodrugs include advanced oral forms or hydrophobic derivatives with superior bio-availability [14][15][16]. However, successful applications of this approach using NTP only include covalent phospholipid conjugates of anti-HIV drug, 3′-azidothymidine (AZT) demonstrating a higher bioavailability and lower toxicity than AZT [17].…”

Section: The Active Form Of Nucleoside Analogs Is Nucleoside 5′-triphmentioning

confidence: 99%

Polymeric nanogel formulations of nucleoside analogs

Vinogradov

2006

Expert Opinion on Drug Delivery

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Nanogels are colloidal microgel carriers that have been introduced recently as a prospective drug delivery system for nucleotide therapeutics. The crosslinked protonated polymer network of nanogels binds oppositely charged drug molecules, encapsulating them into submicron particles with a coreshell structure. The nanogel network also provides a suitable template for chemical engineering, surface modification and vectorisation. This review reveals recent attempts to develop novel drug formulations of nanogels with antiviral and antiproliferative nucleoside analogs in the active form of 5′-triphosphates; discusses structural approaches to the optimisation of nanogel properties, and; discusses the development of targeted nanogel drug formulations for systemic administration. Notably, nanogels can improve the CNS penetration of nucleoside analogs that are otherwise restricted from passing across the blood-brain barrier. The latest findings reviewed here demonstrate an efficient intracellular release of nucleoside analogs, encouraging further applications of nanogel carriers for targeted drug delivery.

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Section: The Active Form Of Nucleoside Analogs Is Nucleoside 5′-triphmentioning

confidence: 99%

Polymeric nanogel formulations of nucleoside analogs

Vinogradov

2006

Expert Opinion on Drug Delivery

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“…[1][2][3][4] Two main approaches have been envisaged requiring either structural modifications or introduction of transient groups. In the first case, a specific enzymatic system is needed to perform the bioconversion of the structurally modified phosphorylated precursor.…”

Section: Introductionmentioning

confidence: 99%

S-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs

et al. 2003

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The synthesis and in vitro anti-HIV activity of phosphoramidate diester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing one S-pivaloyl-2-thioethyl (tBuSATE) group and various amino residues are reported. These compounds were obtained from an H-phosphonate strategy using an amidative oxidation step. Most of these derivatives appeared to inhibit HIV-1 replication, with EC(50) values at micromolar concentration in thymidine kinase-deficient (TK-) cells, revealing a less restrictive intracellular decomposition process than previously reported for other phosphoramidate prodrugs. The proposed decomposition pathway of this new series of mixed pronucleotides may successively involve an esterase and a phosphoramidase hydrolysis.

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“…The best example is the reverse transcriptase from human immunodeficiency virus (5,22,23,28,47,49). In most cases, (deoxy)nucleoside analogs that enter the clinic exploit the relaxed fidelity of viral polymerases relative to those of related cellular polymerases (3,10,15,23,28,30,33,43,47).…”

mentioning

confidence: 99%

Determinants of RNA-Dependent RNA Polymerase (In)fidelity Revealed by Kinetic Analysis of the Polymerase Encoded by a Foot-and-Mouth Disease Virus Mutant with Reduced Sensitivity to Ribavirin

Arias

Arnold

Sierra

et al. 2008

J Virol

113

123

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A mutant poliovirus (PV) encoding a change in its polymerase (3Dpol) at a site remote from the catalytic center (G64S) confers reduced sensitivity to ribavirin and forms a restricted quasispecies, because G64S 3Dpol is a high-fidelity enzyme. A foot-and-mouth disease virus (FMDV) mutant that encodes a change in the polymerase catalytic site (M296I) exhibits reduced sensitivity to ribavirin without restricting the viral quasispecies. In order to resolve this apparent paradox, we have established a minimal kinetic mechanism for nucleotide addition by wild-type (WT) FMDV 3Dpol that permits a direct comparison to PV 3Dpol as well as to FMDV 3Dpol derivatives. Rate constants for correct nucleotide addition were on par with those of PV 3Dpol, but apparent binding constants for correct nucleotides were higher than those observed for PV 3Dpol. The A-to-G transition frequency was calculated to be 1/20,000, which is quite similar to that calculated for PV 3Dpol. The analysis of FMDV M296I 3Dpol revealed a decrease in the calculated ribavirin incorporation frequency (1/8,000) relative to that (1/4,000) observed for the WT enzyme. Unexpectedly, the A-to-G transition frequency was higher (1/8,000) than that observed for the WT enzyme. Therefore, FMDV selected a polymerase that increases the frequency of the misincorporation of natural nucleotides while specifically decreasing the frequency of the incorporation of ribavirin nucleotide. These studies provide a mechanistic framework for understanding FMDV 3Dpol structure-function relationships, provide the first direct analysis of the fidelity of FMDV 3Dpol in vitro, identify the ␤9-␣11 loop as a (in)fidelity determinant, and demonstrate that not all ribavirin-resistant mutants will encode high-fidelity polymerases.

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Design of Anti-HIV Compounds from Nucleoside to Nucleoside 5-Triphosphate Analogs. Problems and Perspectives

Cited by 52 publications

References 54 publications

Polymeric nanogel formulations of nucleoside analogs

Polymeric nanogel formulations of nucleoside analogs

S-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs

Determinants of RNA-Dependent RNA Polymerase (In)fidelity Revealed by Kinetic Analysis of the Polymerase Encoded by a Foot-and-Mouth Disease Virus Mutant with Reduced Sensitivity to Ribavirin

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