Recent Advances in Antiviral Nucleoside and Nucleotide Therapeutics

Simons, Claire; Wu, Qin‐Pei; Htar, Thet Thet

doi:10.2174/156802605774463051

Cited by 48 publications

(27 citation statements)

References 70 publications

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“…These receptors are involved in regulating health and disease [16], including neuroprotection and neurodegeneration [17]–[20], such as ischemia, epilepsy, depression, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington's disease (HD). Therefore, due to the close connections of these purinoreceptors in regulating diverse physiological and pathological neuronal functions, recent advances in therapies using purinergic-related drugs in a wide range of pathological conditions have occurred [18], [21]–[23]. In addition, 6-benzyladenine can act on the P2 receptor [9], and almost all cytokinins are present in plants as both a free base and corresponding nucleosides and nucleotides [24] which have similar adenosine-based structures as agonists of P1 receptors.…”

Section: Introductionmentioning

confidence: 99%

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

et al. 2012

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It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12) cells from serum deprivation-induced apoptosis by acting on the adenosine A2A receptor (A2A-R), which was blocked by an A2A-R antagonist and a protein kinase A (PKA) inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A2A-R signaling event. Since the A2A-R was implicated as a therapeutic target in treating Huntington’s disease (HD), a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt)-induced protein aggregations and proteasome deactivation through A2A-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A2A-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders.

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Section: Introductionmentioning

confidence: 99%

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

et al. 2012

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“…In the following reaction 3 was condensed to the free 5 0 -hydroxyl group of 3 0 -azido-3 0 -deoxythymidine (AZT, 4) which was isolated from expired capsules (Zidovudine TM , Combivir TM ). 2 The condensation was performed in the presence of pivaloyl chloride according to the hydrogenphosphonate method. The phosphonodiester linkage of the condensation product was immediately oxidized with iodine to yield the fully protected octadecylglycerol-AZT conjugate linking the lipophilic glycerol derivative to AZT by a phosphodiester bond.…”

Section: Synthetic Chemistrymentioning

confidence: 99%

“…1,2 The successful clinical application of new antiviral drugs, however, is often limited as compounds with high in vitro activity do not meet the high expectations made for drug development and licensing. An alternative to the search for new single agents inhibiting virus replication lies in the optimization of therapies by combining several well-known antiviral single drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro activities of a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via an octadecylglycerol residue

Schott

Hamprecht

Schott

et al. 2009

Bioorganic & Medicinal Chemistry

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To prepare a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via a lipophilic octadecylglycerol residue we condensed 1-O-4-monomethoxytrityl-3-O-octadecyl-sn-glycerol-2-hydrogenphosphonate obtained from 3-O-octadecyl-sn-glycerol with AZT by the phosphonate method. The purified condensation product was de-tritylated resulting in 3-azido-3-deoxythymidylyl-(5 → 2-O)-3-O-octadecyl-sn-glycerol, followed by treatment with (ethoxycarbonyl)phosphoric dichloride. The resulting 3-azido-3-deoxy-thymidylyl-(5 → 2)-3-O-octadecyl-sn-glycerol-1-O-(ethoxycarbonyl)phosphonate was purified by preparative RP-18 column chromatography. The antiviral duplex drug 3-azido-3-deoxythymidylyl-(5 → 2-O)-3-O-octadecyl-sn-glycerol-1-O-phosphonoformate trisodium salt (AZT-lipid-PFA) was obtained after alkaline cleavage of the phosphonoformate ethylester residue. The overall yield of the five step synthesis performed at gram scale was about 30%. According to a supposed pathway AZT-lipid-PFA could be cleaved to yield a mixture of different antiviral compounds such as AZT, AZT-5-monophosphate, octadecylglycerol-AZT, PFA and octadecylglycerol-PFA, possibly producing additive and/or synergistic antiviral effects. In vitro studies showed that the duplex drug exhibits antiviral activities against HIV and especially against drug-resistant strains and clinical isolates of HSV and HCMV. The E50 values of AZT-lipid-PFA against HIV ranged between 170 and 200 nM. The half-maximal inhibitory doses (IC50) against highly acyclovir (ACV)-resistant HSV isolates determined by a plaque reduction assay ranged between 1.87 and 4.59 M. Using ganciclovir (GCV)-sensitive, GCV resistant and drug cross-resistant HCMV strains the IC50-values of AZT-lipid-PFA were between 2.78 and 1.18 M. With regard to PFA, the IC50-value of AZT-lipid-PFA determined on a multi-drug-resistant HCMV strain was about 90-fold lower than that of PFA, demonstrating the superior antiviral effect of the duplex-drug. 0 -monophosphate, octadecylglycerol-AZT, PFA and octadecylglycerol-PFA, possibly producing additive and/or synergistic antiviral effects. In vitro studies showed that the duplex drug exhibits antiviral activities against HIV and especially against drug-resistant strains and clinical isolates of HSV and HCMV. The E 50 values of AZT-lipid-PFA against HIV ranged between 170 and 200 nM. The half-maximal inhibitory doses (IC 50 ) against highly acyclovir (ACV)-resistant HSV isolates determined by a plaque reduction assay ranged between 1.87 and 4.59 lM. Using ganciclovir (GCV)-sensitive, GCV resistant and drug cross-resistant HCMV strains the IC 50 -values of AZT-lipid-PFA were between 2.78 and 1.18 lM. With regard to PFA, the IC 50 -value of AZT-lipid-PFA determined on a multi-drug-resistant HCMV strain was about 90-fold lower than that of PFA, demonstrating the superior antiviral effect of the duplex-drug.

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“…Many nucleoside analogues are currently used as antiviral [1,2], antineoplastic [3,4,5,6] and antifungal [7,8,9] agents. Numerous nucleoside derivatives interact with enzymes such as CD38 [10] or 5'-AMP-activated protein kinase (AMPK), playing a key role in the signal transduction or regulation of energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

Solid-Phase Synthesis of a New Diphosphate 5-Aminoimidazole-4-carboxamide Riboside (AICAR) Derivative and Studies toward Cyclic AICAR Diphosphate Ribose

et al. 2011

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The solid-phase synthesis of the first example of a new diphosphate AICAR derivative is reported. The new substance is characterized by the presence of a 5'-phosphate group while a second phosphate moiety is installed on a 5-hydroxypentyl chain attached to the 4-N-position of AICAR. Cyclization of the diphosphate derivative by pyrophosphate bond formation allowed for the formation of a novel AICAR-based cyclic ADP-ribose (cADPR) mimic.

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Recent Advances in Antiviral Nucleoside and Nucleotide Therapeutics

Cited by 48 publications

References 70 publications

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

Synthesis and in vitro activities of a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via an octadecylglycerol residue

Solid-Phase Synthesis of a New Diphosphate 5-Aminoimidazole-4-carboxamide Riboside (AICAR) Derivative and Studies toward Cyclic AICAR Diphosphate Ribose

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