Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination
Norbert PardiMichael J. HoganRebecca S. PelcHiromi MuramatsuHanné AndersenChristina R. DeMasoKimberly A. DowdLaura L. SutherlandRichard M. ScearceRobert ParksWendeline WagnerAlex GranadosJack GreenhouseMichelle WalkerElinor WillisJae-Sung YuCharles E. McGeeGregory D. SempowskiBarbara L. MuiYing K. TamYan-Jang Scott HuangDana L. VanlandinghamVeronica M. HolmesHarikrishnan BalachandranSujata SahuMichelle A. LiftonStephen HiggsScott E. HensleyThomas D. MaddenMichael J. HopeKatalin KarikóSampa SantraBarney S. GrahamMark G. LewisTheodore C. PiersonBarton F. HaynesDrew Weissman
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Zika Virus
Nucleoside analogue
Combination antiretroviral drug treatments depend on 3′-deoxy-nucleoside analogs such as 3′-azido-3′-deoxythymidine (AZT) and 2′3′-dideoxyinosine (DDI). Despite being effective in inhibiting human immunodeficiency virus replication, these drugs produce a range of toxicities, including myopathy, pancreatitis, neuropathy, and lactic acidosis, that are generally considered as sequelae to mitochondrial damage. Although cell surface–localized nucleoside transporters, such as human equilibrative nucleoside transporter 2 (hENT2) and human concentrative nucleoside transporter 1 (hCNT1), are known to increase the carrier-mediated uptake of 3′-deoxy-nucleoside analogs into cells, another ubiquitously expressed intracellular nucleoside transporter (namely, hENT3) has been implicated in the mitochondrial transport of 3′-deoxy-nucleoside analogs. Using site-directed mutagenesis, generation of chimeric hENTs, and 3H-permeant flux measurements in mutant/chimeric RNA–injected Xenopus oocytes, here we identified the molecular determinants of hENT3 that dictate membrane translocation of 3′-deoxy-nucleoside analogs. Our findings demonstrated that whereas hENT1 had no significant transport activity toward 3′-deoxy-nucleoside analogs, hENT3 was capable of transporting 3′-deoxy-nucleoside analogs similar to hENT2. Transport analyses of hENT3-hENT1 chimeric constructs demonstrated that the N-terminal half of hENT3 is primarily responsible for the hENT3–3′-deoxy-nucleoside analog interaction. In addition, mutagenic studies identified that 225D and 231L in the N-terminal half of hENT3 partially contribute to the ability of hENT3 to transport AZT and DDI. The identification of the transporter segment and amino acid residues that are important in hENT3 transport of 3′-deoxy-nucleoside analogs may present a possible mechanism for overcoming the adverse toxicities associated with 3′-deoxy-nucleoside analog treatment and may guide rational development of novel nucleoside analogs.
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Concentrative nucleoside transporters (CNTs) are responsible for cellular entry of nucleosides, which serve as precursors to nucleic acids and act as signaling molecules. CNTs also play a crucial role in the uptake of nucleoside-derived drugs, including anticancer and antiviral agents. Understanding how CNTs recognize and import their substrates could not only lead to a better understanding of nucleoside-related biological processes but also the design of nucleoside-derived drugs that can better reach their targets. Here, we present a combination of X-ray crystallographic and equilibrium-binding studies probing the molecular origins of nucleoside and nucleoside drug selectivity of a CNT from Vibrio cholerae. We then used this information in chemically modifying an anticancer drug so that it is better transported by and selective for a single human CNT subtype. This work provides proof of principle for utilizing transporter structural and functional information for the design of compounds that enter cells more efficiently and selectively.
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Purine nucleoside analogues are extensively used in the treatment of malignancies and viral diseases. For example, cladribine and fludarabine are two purine nucleoside analogues that have activity in the treatment of chronic lymphocytic leukemias. These chemotherapeutic agents exert their cytotoxic actions through interactions with intracellular targets. Due to their hydrophilic nature, many purine nucleoside analogues do not readily diffuse across cell membranes at therapeutic concentrations. The presence or absence of mediated transport systems will therefore have an impact on their pharmacological activities. There are two families of nucleoside transporters with members in human (h) cells and tissues: the equilibrative nucleoside transporters (hENTs) and the concentrative nucleoside transporters (hCNTs). These transporter proteins mediate the uptake of both physiologic nucleosides and nucleoside analogue chemotherapeutic agents. It has been documented that permeant specificity, tissue distribution and cellular localization of these transporters contribute to the antineoplastic activity of the purine nucleoside analogues. This article will review current knowledge of the role of nucleoside transport proteins in the cytotoxic actions of purine nucleoside analogues. Keywords: Anti-cancer purine nucleoside analogues, nucleoside transporters
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Many anticancer and antiviral drugs are nucleoside analogues, which interfere with nucleotide metabolism and DNA replication to produce pharmacological effects. Clinical efficacy and toxicity of nucleoside drugs are closely associated with nucleoside transporters because they mediate the transport of nucleoside drugs across biological membranes. Two families of human nucleoside transporters (equilibrative nucleoside transporters and concentrative nucleoside transporters) have been extensively studied for several decades. They are widely distributed, from the plasma membrane to membranes of organelles such as mitochondria, and the distribution differs in different tissues. In addition, they have different specificities to nucleoside drugs. The characteristics of equilibrative and concentrative nucleoside transporters affect the therapeutic outcomes achieved with anticancer and antiviral nucleoside drugs. In this review, an overview of the role of mitochondrial and plasma membrane nucleoside transporters in nucleoside drug toxicity is provided. Rational design and therapeutic application of nucleoside analogues are also discussed.
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In recent years, some HBV strains resistant to nucleoside analogs have occurred in the treatment of hepatitis B. This review summarizes the application of nucleoside analogs in the treatment of HBV infection, the mechanism, detection and control methods of the resistance to nucleoside analogs.
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Hepatitis B virus; Drug resistance; Nucleoside analogs
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This review describes recent advances in developing human nucleoside transporters (hNTs) as biomarkers to predict response to nucleoside analog drugs with clinical activity. Understanding processes that contribute to drug response or lack thereof will provide strategies to potentiate efficacy or avoid toxicities of nucleoside analog drugs. hNT abundance, evaluated by immunohistochemical methods, has shown promise as a predictive marker to assess clinical drug response that could be used to identify patients who would most likely benefit from nucleoside analog drug treatment.
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Many anticancer and antiviral drugs are nucleoside analogues, which interfere with nucleotide metabolism and DNA replication to produce pharmacological effects. Clinical efficacy and toxicity of nucleoside drugs are closely associated with nucleoside transporters because they mediate the transport of nucleoside drugs across biological membranes. Two families of human nucleoside transporters (equilibrative nucleoside transporters and concentrative nucleoside transporters) have been extensively studied for several decades. They are widely distributed, from the plasma membrane to membranes of organelles such as mitochondria, and the distribution differs in different tissues. In addition, they have different specificities to nucleoside drugs. The characteristics of equilibrative and concentrative nucleoside transporters affect the therapeutic outcomes achieved with anticancer and antiviral nucleoside drugs. In this review, an overview of the role of mitochondrial and plasma membrane nucleoside transporters in nucleoside drug toxicity is provided. Rational design and therapeutic application of nucleoside analogues are also discussed.
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Mitochondrial toxicity
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