Anti-(herpes simplex virus) activity of 4′-thio-2′-deoxyuridines: a biochemical investigation for viral and cellular target enzymes

Verri, Annalisa; Focher, Federico; Duncombe, R. J.; Bašnák, I.; Walker, Richard; Coe, Paul L.; Clercq, Erik De; Andrei, Gracíela; Snoeck, Robert; Balzarini, Jan; Spadari, Silvio

doi:10.1042/bj3510319

Cited by 14 publications

(8 citation statements)

References 17 publications

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“…Although most T-dCyd was converted to T-dUrd, there was little evidence that T-dUrd was phosphorylated by dThd kinase and then converted to T-TMP via thymidylate synthase: 12% of dCyd was converted to dThd nucleotides in HCT116 cells, however, only 0.2% of T-dCyd was converted to T-dThd nucleotides. This observation supports previous studies (Secrist et al, 1991;Verri et al, 2000) that indicated T-dUrd was a poor substrate for dThd kinase. In addition, T-dUrd was not a substrate for dThd phosphorylase in crude cell extracts of .…”

Section: Metabolism and Depletion Of Dnmt1 By T-dcydsupporting

confidence: 92%

5-Aza-4′-thio-2′-deoxycytidine, a New Orally Bioavailable Nontoxic “Best-in-Class”: DNA Methyltransferase 1–Depleting Agent in Clinical Development

Parker¹,

Thottassery²

2021

J Pharmacol Exp Ther

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DNA methyltransferase 1 (DNMT1) is an enzyme that functions as a maintenance methyltransferase during DNA replication, and depletion of this enzyme from cells is considered to be a rational goal in DNA methylation dependent disorders. Two DNMT1 depleting agents aza-dCyd (5-aza-2'-deoxycytidine, decitabine) and aza-Cyd (5-aza-cytidine, azacitidine) are currently used for the treatment of myelodysplastic syndromes and acute myeloid leukemia, and have also been investigated for non-oncology indications such as sickle cell disease. However, these agents have several off-target activities leading to significant toxicities that limit dosing and duration of treatment. Development of more selective inhibitors of DNMT1 could therefore afford treatment for long durations at effective doses. We have discovered that 5-aza-4'-thio-2'deoxycytidine (aza-T-dCyd) is as effective as aza-dCyd in depleting DNMT1 in mouse tumor models, but with markedly low toxicity. In this review we describe the preclinical studies that led to the development of aza-T-dCyd as a superior DNMT1 depleting agent with respect to aza-dCyd, and will describe its pharmacology, metabolism, and mechanism of action. In an effort to understand why aza-T-dCyd is a more selective DNMT1 depleting agent than aza-dCyd, we will also compare and contrast the activities of these two agents. Significance Statement.Aza-T-dCyd is a potent DNMT1 depleting agent. Although similar in structure to decitabine (aza-dCyd) its metabolism and mechanism of action is different than that of aza-dCyd, resulting in less off target activity and less toxicity. The larger therapeutic index of aza-T-dCyd (DNMT1 depletion vs toxicity) in mice suggests that it would be a better clinical candidate to selectively deplete DNMT1 from target cells and determine whether or not depletion of DNMT1 is an effective target for various diseases.

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Section: Metabolism and Depletion Of Dnmt1 By T-dcydsupporting

confidence: 92%

5-Aza-4′-thio-2′-deoxycytidine, a New Orally Bioavailable Nontoxic “Best-in-Class”: DNA Methyltransferase 1–Depleting Agent in Clinical Development

Parker¹,

Thottassery²

2021

J Pharmacol Exp Ther

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“…Although they all likely act on the viral DNA Pol, further investigation will be required to substantiate this. Such would be the case, for example, for derivatives of acyclic/carbocyclic guanosine analogs [219], 4'-thio-2'-deoxyuridines [220]. (1S',2R')-9-[[1',2'-bis(hydroxymethyl)cycloprop-1-yl]methyl]guanine (A-5021) [221], cyclohexenylguanine [222], 5-alkyl-2-thiopyrimidine nucleosides [223], conformationally locked (north)-methanocarbathymine nucleosides [224], acyclic C-nucleoside analogs of 2,6-dichloro-and 2,6,7-trichloroimidazo [225] pyridine [226], methylenecyclopropane analogs of nucleosides [227], 3 -formyl -2, 5, 6 -trichloro -1 -( beta -D -ribofuranosyl) indole (FTCRI) and its 3-cyano homologue (CTCRI) at the 3-position, chlorinated nucleosides pyrazolo [228] indole nucleoside analogs.…”

Section: Perspectives For Drug Designmentioning

confidence: 99%

Antiviral Therapy Targeting Viral Polymerase

Tsai

Lee²,

Stollar³

et al. 2006

CPD

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Viral DNA and RNA polymerases are enzymes, which are responsible for copying the genetic materials of viruses and are therefore central components in the life cycles of viruses. The polymerases are essentially required for the replication of viruses. The reverse transcriptase (RT) of the retroviruses and the hepadnaviruses is the sole viral enzyme required for the synthesis of DNA from viral RNA. Viral polymerases are therefore an extremely favorable target for the development of antiviral therapy. The success of anti-HIV-1 therapy using inhibitors specifically targeting HIV RT suggests that other viral polymerases can be the valid molecular targets for the design of antiviral drugs. Intensive structural and functional studies of viral polymerases have been conducted and have opened new avenues for the development of more effective antiviral therapy. This review summarizes the insights gained from recent structural and functional studies of antiviral agents, which target viral polymerases. The primary focus will be on hepatitis C virus (HCV), herpesviruses, HIV, hepatitis B virus (HBV) and influenza virus.

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“…The synthesis of 2'-deoxy-4'-thiouridines, which exhibit an anti-HSV activity significantly higher (20-600 times) than that shown by the corresponding 4'-oxo counterpart, is one of attempts to avoid this degradation. Verri et al [35] have synthesized 5-substituted 2'-deoxy-4'-thiouridines ( Fig. 3-1) according to the procedure previously described by Rahim et al [25] and investigated their mode of actions.…”

Section: ' or 3'-deoxy-4'-thionucleosidesmentioning

confidence: 99%

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

Gunaga¹,

Moon²,

Choi³

et al. 2004

CMC

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The classical 4'-oxonucleoside analogs exhibit interesting biological activities such as antibiotic, antiviral and antitumor, which are believed to be the result of inhibition of the viral or cellular DNA or RNA polymerase after being converted to their corresponding 5'-triphosphates. However, the activity of 4'-oxonucleosides were limited by their susceptibility to degradation by nucleoside phosphorylases or acid hydrolysis. This aspect called for the chemical modification of the carbohydrate portion. This compulsion led to two kinds of strategies; (1) replacement of the 4'-oxygen by the methylene group - carbocyclic nucleosides; (2) replacement of the 4' oxygen by sulphur-4'-thionucleosides. This group has also conferred the resistance to the nucleoside cleavage. Although, there were some pioneering work on 4'-thionucleosides in 1960s and 1970s, the interest in this group of compounds was rekindled by the antiviral activities of 2'-deoxy-4'-thionucleosides reported independently by Secrist et al. and Walker et al. Subsequent contributions by the other authors, enhanced its standing as an important class of antiviral agents. Following is a reasonably exhaustive account of this class of compounds reported after 1990.

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Anti-(herpes simplex virus) activity of 4′-thio-2′-deoxyuridines: a biochemical investigation for viral and cellular target enzymes

Cited by 14 publications

References 17 publications

5-Aza-4′-thio-2′-deoxycytidine, a New Orally Bioavailable Nontoxic “Best-in-Class”: DNA Methyltransferase 1–Depleting Agent in Clinical Development

5-Aza-4′-thio-2′-deoxycytidine, a New Orally Bioavailable Nontoxic “Best-in-Class”: DNA Methyltransferase 1–Depleting Agent in Clinical Development

Antiviral Therapy Targeting Viral Polymerase

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

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