Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

Chemical Reviews, Journal Year: 2016, Volume and Issue: 116(23), P. 14379 - 14455

Published: Nov. 23, 2016

Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens neoplasms. More than 20% of patients on anticancer chemotherapy treated with one or more these analogs. This review focuses chemical synthesis biology nucleoside, that are FDA-approved clinical development since 2000. We highlight cellular analogs, drug resistance mechanisms, compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well improved scale-up syntheses. conclude a discussion what might lie ahead medicinal chemists, biologists, physicians they try improve efficacy through prodrug strategies combinations.

Language: Английский

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The ribonuclease activity of SAMHD1 is required for HIV-1 restriction

Nature Medicine, Journal Year: 2014, Volume and Issue: 20(8), P. 936 - 941

Published: July 16, 2014

Language: Английский

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SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

Cell Reports, Journal Year: 2017, Volume and Issue: 20(8), P. 1921 - 1935

Published: Aug. 1, 2017

Highlights•SAMHD1 deficiency or Vpx-mediated degradation sensitizes cells to DSB-inducing agents•SAMHD1 localizes DNA double-strand breaks in response damage•SAMHD1 promotes HR and end resection independent of its dNTPase activity•SAMHD1 complexes with CtIP facilitates recruitment damage sitesSummaryDNA break (DSB) repair by homologous recombination (HR) is initiated CtIP/MRN-mediated maintain genome integrity. SAMHD1 a dNTP triphosphohydrolase, which restricts HIV-1 infection, mutations are associated Aicardi-Goutières syndrome cancer. We show that has dNTPase-independent function promoting facilitate DSB HR. causes hypersensitivity agents, recruited DSBs. via conserved C-terminal domain recruits DSBs Significantly, cancer-associated mutant impaired interaction, but not dNTPase-inactive SAMHD1, fails rescue the impairment depletion. Our findings define for HR-mediated facilitating accrual promote resection, providing insight into how integrity.Graphical abstract

Language: Английский

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SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 17, 2025

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism SAMHD1, which involves dNTP binding at allosteric sites transient tetramerization. Our findings reveal tetramerization alone insufficient to promote hydrolysis; instead, requires an inactive tetrameric intermediate with partially occupied sites. The equilibrium between active states regulates activity, driven by dissociation additional ligands preassembled tetramer. Furthermore, catalytic efficiency, but not specificity, modulated identity dNTPs occupying We show how this regulation shapes deoxynucleotide homeostasis balancing production SAMHD1-catalyzed depletion. Notably, exhibits distinct functionality, term facilitated depletion, whereby increased biosynthesis certain enhances depletion others. regulatory relationship different sheds light on emerging role biology implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Language: Английский

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Structural basis of cellular dNTP regulation by SAMHD1

Proceedings of the National Academy of Sciences, Journal Year: 2014, Volume and Issue: 111(41)

Published: Sept. 29, 2014

Significance SAMHD1 is a dNTPase that depletes the cellular dNTP pool to inhibit replication of retroviruses, including HIV-1. The activity also enables enzyme be major regulator levels in mammalian cells, addition implicated pathogenesis chronic lymphocytic leukemia (CLL) and Aicardi Goutières syndrome (AGS). Here we present extensive structural enzymatic data reveal how activated regulated via combined actions GTP all dNTPs. Our work establishes complete spectrum nucleotide binding exquisite regulatory mechanism metabolism, retrovirus restriction, CLL AGS.

Language: Английский

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SAMHD1 is a single-stranded nucleic acid binding protein with no active site-associated nuclease activity

Nucleic Acids Research, Journal Year: 2015, Volume and Issue: 43(13), P. 6486 - 6499

Published: June 22, 2015

The HIV-1 restriction factor SAMHD1 is a tetrameric enzyme activated by guanine nucleotides with dNTP triphosphate hydrolase activity (dNTPase). In addition to this established activity, there have been series of conflicting reports as whether the also possesses single-stranded DNA and/or RNA 3′-5′ exonuclease activity. was purified using three chromatography steps, over which DNase largely separated from dNTPase but RNase persisted. Surprisingly, we found that catalytic and nucleotide activator site mutants no retained activities. Thus, cannot be associated any known binding site. Monomeric bind preferentially RNA, while form required for action bound weakly. ssRNA binding, not ssDNA, induces higher-order oligomeric states are distinct binds dNTPs. We conclude trace activities detected in preparations arise persistent contaminants co-purify HD active An vivo model suggested where alternates between mutually exclusive functions hydrolysis depending on pool levels presence viral ssRNA.

Language: Английский

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Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications

Molecular Cancer, Journal Year: 2015, Volume and Issue: 14(1)

Published: Sept. 29, 2015

Regulation of intracellular deoxynucleoside triphosphate (dNTP) pool is critical to genomic stability and cancer development. Imbalanced dNTP pools can lead enhanced mutagenesis cell proliferation resulting in Therapeutic agents that target synthesis metabolism are commonly used treatment several types cancer. Despite studies, the molecular mechanisms regulate levels maintain their homeostasis not completely understood. The discovery SAMHD1 as first mammalian triphosphohydrolase provided new insight into regulation. maintains homeostatic DNA replication damage repair. Recent progress indicates gene mutations epigenetic downregulation activity or expression multiple cancers. Impaired function cause increased instability cell-cycle progression, thereby facilitating proliferation. This review summarizes latest advances understanding importance development novel regulating this process.

Language: Английский

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SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(16)

Published: April 2, 2018

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) blocks replication of retroviruses certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN inflammatory responses viral infections, although functions mechanisms in modulating innate immunity remain unclear. Here, we show that suppresses immune infections stimuli inhibiting nuclear factor-κB (NF-κB) activation type I interferon (IFN-I) induction. Compared with control cells, infection SAMHD1-silenced human monocytic cells or primary macrophages Sendai virus (SeV) HIV-1, treatment stimuli, induces significantly higher levels NF-κB IFN-I Exogenous expression reconstitution knockout induction SeV stimuli. Mechanistically, inhibits interacting NF-κB1/2 phosphorylation inhibitory IκBα. also interacts inhibitor-κB kinase ε (IKKε) regulatory factor 7 (IRF7), leading suppression pathway IKKε-mediated IRF7 phosphorylation. Interactions endogenous proteins were validated macrophages. Comparing splenocytes from heterozygous mice, further confirmed SAMHD1-mediated activation, suggesting an evolutionarily conserved property SAMHD1. Our findings reveal down-regulating highlighting importance antiviral immunity.

Language: Английский

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Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction

PLoS Pathogens, Journal Year: 2015, Volume and Issue: 11(10), P. e1005194 - e1005194

Published: Oct. 2, 2015

SAMHD1 restricts HIV-1 infection of myeloid-lineage and resting CD4+ T-cells. Most likely this occurs through deoxynucleoside triphosphate triphosphohydrolase activity that reduces cellular dNTP to a level where reverse transcriptase cannot function, although alternative mechanisms have been proposed recently. Here, we present combined structural virological data demonstrating in addition allosteric activation activity, restriction correlates with the capacity form "long-lived" enzymatically competent tetramers. Tetramer disruption invariably abolishes but has varied effects on vitro activity. phosphorylation also ablates tetramer formation without affecting steady-state kinetics. However phospho-SAMHD1 is unable catalyse turnover under conditions nucleotide depletion. Based our findings propose model for phosphorylation-dependent regulation dephosphorylation switches housekeeping found cycling cells high-activity stable tetrameric depletes maintains low levels dNTPs differentiated cells.

Language: Английский

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Insights into catalysis and function of phosphoribosyl-linked serine ubiquitination

Nature, Journal Year: 2018, Volume and Issue: 557(7707), P. 734 - 738

Published: May 1, 2018

Language: Английский

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