Inhibition of Human Immunodeficiency Virus (HIV) Production by 5′-Hydrogenphosphonates of 3′-Azido-2′,3′- dideoxynucleosides

Tarussqva, Natalya B.; Kukhanova, Marina K.; Krayevsky, Alexander A.; Karamov, Edward K.; Lukashov, Vladimir V.; Kornilayeva, Galina B.; Rodina, M A; Galecov, Georgii A.

doi:10.1080/07328319108046477

Cited by 23 publications

(7 citation statements)

References 5 publications

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“…This assertion was corroborated by the inability to detect AZT-MP upon incubation of the dimeric AZT 5 H -5 H linked H-phosphonate in medium containing 10% FCS, which instead generated AZT and AZT H-phosphonate. 158 In contrast, Boal and co-workers 159 reported that AZT 5 H -H phosphonate gave rise to AZT-MP in human pleural effusion leukemia U937 cells and that the phosphonate was not converted to AZT by 5 H -nucleotidase.…”

Section: E H-phosphonate Derivativesmentioning

confidence: 98%

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Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Wagner¹,

Iyer²,

McIntee³

2000

Med. Res. Rev.

264

215

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To overcome the many hurdles preventing the use of antiviral and anticancer nucleosides as therapeutics, the development of a prodrug methodology (i.e., pronucleotide) for the in vivo delivery of nucleotides has been proposed as a solution. The ideal pronucleotide should be non‐toxic, stable in plasma and blood, capable of being i.v. and/or orally dosed, and intracellularly convertible to the corresponding nucleotide. Although this goal has yet to be achieved, many clever and imaginative pronucleotide approaches have been developed, which are likely to be important pharmacological tools. This review will discuss the major advances and future directions of the emerging field of antiviral and anticancer pronucleotide design and development. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 6, 417–451, 2000

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Section: E H-phosphonate Derivativesmentioning

confidence: 98%

“…The 5 H -H phosphonates of thymidine, adenosine, guanosine, and cytosine were found to inhibit HIV-1 production by MT-4 cells. 159…”

Section: E H-phosphonate Derivativesmentioning

confidence: 99%

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Wagner¹,

Iyer²,

McIntee³

2000

Med. Res. Rev.

264

215

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“…The study of molecular mechanism of nucleoside 5'-(amethylphosphonyl)-(,,y-diphosphates action in the cell-free systems is reasonable because several 5'-phosphonates of sugarmodified nucleosides demonstrated their high inhibitory activity against HIV reproduction in cell cultures [8][9][10][11]. One of the possible mechanisms of action of 5'-phosphonates is the transformation of such nucleotides into the 3,,y-diphosphate derivatives with following DNA chain elongation either by termination or competitive inhibition by the substrate, or both ways simultaneously.…”

Section: Introductionmentioning

confidence: 99%

Formation of phosphonester bonds catalyzed by DNA polymerase

et al. 1992

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3'-Fluoro-2',3'-dideoxythymidine 5'-(alpha-methylphosphonyl)-beta,gamma- diphosphate and 2'-deoxythymidine-5'-(alpha-methylphosphonyl)-beta, gamma- diphosphate have been synthesized. Both compounds are incorporated into DNA chains during catalysis by reverse transcriptases of human immunodeficiency (HIV) and avian myeloblastosis (AMV) viruses, DNA polymerase beta from rat liver, terminal deoxynucleotidyl transferase from calf thymus and (at a very low rate) is by E. coli DNA polymerase I, Klenow fragment. The first compound is a termination substrate while the second is capable of multiple incorporation into the DNA chains. For instance, reverse transcriptase catalysis resulted in the appearance of 8 residues of second compound. DNA polymerases alpha and epsilon from human placenta incorporated none of the above compounds into DNA chains, although an inhibition of DNA synthesis by both compounds was observed with all enzymes mentioned. The 3'----5'-exonuclease activity of DNA polymerase I, Klenow fragment, hydrolyzed DNA fragments containing phosphonomethyl internucleoside groups, while such DNA fragments were resistant to the E. coli exonuclease III.

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“…It was initially reported that phosphazide 1 exhibited moderate anti-HIV activity and lower toxicity in a MT-4 cell culture as compared to AZT [18, 19]. Its selectivity index was higher than that of AZT.…”

Section: Nikavir (Phosphazide) the First Achievement In Designing Dementioning

confidence: 99%

AZT 5’-Phosphonates: Achievements and Trends in the Treatment and Prevention of HIV Infection

Khandazhinskaya

Shirokova

2013

Acta Naturae

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Despite the numerous drawbacks, 3’-azido-3’-deoxythymidine (AZT, Zidovudine, Retrovir) remains one of the key drugs used in the treatment and prevention of HIV infection in both monotherapy and HAART. A strategy in searching for new effective and safe AZT agents among latent (depot) forms of AZT has yielded its first positive results. In particular, the sodium salt of AZT 5’-H-phosphonate (Nikavir, phosphazide) has demonstrated clinical advantages over parent AZT: first and foremost, lower toxicity and better tolerability. It can be effectively used for the prevention of vertical transmission from mothers to babies and as an alternative drug for HIV-infected patients with low tolerance to Zidovudine. Preclinical studies of another phosphonate, AZT 5’-aminocarbonylphosphonate, have demonstrated that it releases AZT when taken orally. Pharmacokinetic studies have shown a prolonged action potential. Based on the analysis of both toxicological and pharmacological data, AZT 5’-aminocarbonylphosphonate has been recommended for clinical trials.

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Inhibition of Human Immunodeficiency Virus (HIV) Production by 5′-Hydrogenphosphonates of 3′-Azido-2′,3′- dideoxynucleosides

Cited by 23 publications

References 5 publications

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Formation of phosphonester bonds catalyzed by DNA polymerase

AZT 5’-Phosphonates: Achievements and Trends in the Treatment and Prevention of HIV Infection

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