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Annual Review of Pharmacology and Toxicology

Volume 56, 2016

Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells

Abstract

RNA has become an increasingly important target for therapeutic interventions and for chemical probes that dissect and manipulate its cellular function. Emerging targets include human RNAs that have been shown to directly cause cancer, metabolic disorders, and genetic disease. In this review, we describe various routes to obtain bioactive compounds that target RNA, with a particular emphasis on the development of small molecules. We use these cases to describe approaches that are being developed for target validation, which include target-directed cleavage, classic pull-down experiments, and covalent cross-linking. Thus, tools are available to design small molecules to target RNA and to identify the cellular RNAs that are their targets.

Keyword(s): antibacterials, antisense oligonucleotides, genetic disease, Inforna, nucleic acids, orphan disease, rational design, RNA, target identification
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2016-01-06
2024-04-23
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Literature Cited

  1. Batey RT, Rambo RP, Doudna JA. 1.  1999. Tertiary motifs in RNA structure and folding. Angew. Chem. Int. Ed. Engl. 38:2326–43 [Google Scholar]
  2. Doudna JA. 2.  2000. Structural genomics of RNA. Nat. Struct. Biol. 7:Suppl.954–56 [Google Scholar]
  3. Sicot G, Gomes-Pereira M. 3.  2013. RNA toxicity in human disease and animal models: from the uncovering of a new mechanism to the development of promising therapies. Biochim. Biophys. Acta 1832:1390–409 [Google Scholar]
  4. Visone R, Croce CM. 4.  2009. MiRNAs and cancer. Am. J. Pathol. 174:1131–38 [Google Scholar]
  5. Swayze EE, Bhat B. 5.  2008. The medicinal chemistry of oligonucleotides. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke 143–82 Boca Raton, FL: CRC [Google Scholar]
  6. Guan L, Disney MD. 6.  2012. Recent advances in developing small molecules targeting RNA. ACS Chem. Biol. 7:73–86 [Google Scholar]
  7. Gallego J, Varani G. 7.  2001. Targeting RNA with small-molecule drugs: therapeutic promise and chemical challenges. Acc. Chem. Res. 34:836–43 [Google Scholar]
  8. Thomas JR, Hergenrother PJ. 8.  2008. Targeting RNA with small molecules. Chem. Rev. 108:1171–224 [Google Scholar]
  9. Nesterova M, Cho-Chung YS. 9.  2004. Killing the messenger: antisense DNA and siRNA. Curr. Drug Targets 5:683–89 [Google Scholar]
  10. Sierakowska H, Agrawal S, Kole R. 10.  2000. Antisense oligonucleotides as modulators of pre-mRNA splicing. Methods Mol. Biol. 133:223–33 [Google Scholar]
  11. Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V. 11.  2000. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407:340–48 [Google Scholar]
  12. Poehlsgaard J, Douthwaite S. 12.  2005. The bacterial ribosome as a target for antibiotics. Nat. Rev. Microbiol. 3:870–81 [Google Scholar]
  13. Yonath A, Bashan A. 13.  2004. Ribosomal crystallography: Initiation, peptide bond formation, and amino acid polymerization are hampered by antibiotics. Annu. Rev. Microbiol. 58:233–51 [Google Scholar]
  14. Gareiss PC, Sobczak K, McNaughton BR, Palde PB, Thornton CA, Miller BL. 14.  2008. Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA-MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1). J. Am. Chem. Soc. 130:16254–61 [Google Scholar]
  15. Jahromi AH, Nguyen L, Fu Y, Miller KA, Baranger AM, Zimmerman SC. 15.  2013. A novel CUGexp⋅MBNL1 inhibitor with therapeutic potential for myotonic dystrophy type 1. ACS Chem. Biol. 8:1037–43 [Google Scholar]
  16. Childs-Disney JL, Hoskins J, Rzuczek SG, Thornton CA, Disney MD. 16.  2012. Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive. ACS Chem. Biol. 7:856–62 [Google Scholar]
  17. Kumar A, Parkesh R, Sznajder LJ, Childs-Disney JL, Sobczak K, Disney MD. 17.  2012. Chemical correction of pre-mRNA splicing defects associated with sequestration of muscleblind-like 1 protein by expanded r(CAG)-containing transcripts. ACS Chem. Biol. 7:496–505 [Google Scholar]
  18. Tran T, Childs-Disney JL, Liu B, Guan L, Rzuczek S, Disney MD. 18.  2014. Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides. ACS Chem. Biol. 9:904–12 [Google Scholar]
  19. Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J. 19.  et al. 2014. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043–50 [Google Scholar]
  20. Pushechnikov A, Lee MM, Childs-Disney JL, Sobczak K, French JM. 20.  et al. 2009. Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3. J. Am. Chem. Soc. 131:9767–79 [Google Scholar]
  21. Velagapudi SP, Disney MD. 21.  2014. Two-dimensional combinatorial screening enables the bottom-up design of a microRNA-10b inhibitor. Chem. Commun. 50:3027–29 [Google Scholar]
  22. Velagapudi SP, Gallo SM, Disney MD. 22.  2014. Sequence-based design of bioactive small molecules that target precursor microRNAs. Nat. Chem. Biol. 10:291–97 [Google Scholar]
  23. Bose D, Jayaraj G, Suryawanshi H, Agarwala P, Pore SK. 23.  et al. 2012. The tuberculosis drug streptomycin as a potential cancer therapeutic: inhibition of miR-21 function by directly targeting its precursor. Angew. Chem. Int. Ed. Engl. 51:1019–23 [Google Scholar]
  24. Guan L, Disney MD. 24.  2013. Small molecule-mediated cleavage of RNA in living cells. Angew. Chem. Int. Ed. Engl. 52:1462–65 [Google Scholar]
  25. Guan L, Disney MD. 25.  2013. Covalent small molecule-RNA complex formation enables cellular profiling of small molecule-RNA interactions. Angew. Chem. Int. Ed. Engl. 52:10010–13 [Google Scholar]
  26. Stephenson ML, Zamecnik PC. 26.  1978. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. PNAS 75:285–88 [Google Scholar]
  27. Zamecnik PC, Stephenson ML. 27.  1978. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. PNAS 75:280–84 [Google Scholar]
  28. Keller W, Crouch R. 28.  1972. Degradation of DNA RNA hybrids by ribonuclease H and DNA polymerases of cellular and viral origin. PNAS 69:3360–64 [Google Scholar]
  29. Agrawal S. 29.  1999. Importance of nucleotide sequence and chemical modifications of antisense oligo-nucleotides. Biochim. Biophys. Acta 1489:53–68 [Google Scholar]
  30. Arechavala-Gomeza V, Khoo B, Aartsma-Rus A. 30.  2014. Splicing modulation therapy in the treatment of genetic diseases. Appl. Clin. Genet. 7:245–52 [Google Scholar]
  31. Farooqi AA, Rehman ZU, Muntane J. 31.  2014. Antisense therapeutics in oncology: current status. Onco Targets Ther. 7:2035–42 [Google Scholar]
  32. Lorenzer C, Dirin M, Winkler AM, Baumann V, Winkler J. 32.  2015. Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics. J. Control. Release 203:1–15 [Google Scholar]
  33. Lima WF, Monia BP, Ecker DJ, Freier SM. 33.  1992. Implication of RNA structure on antisense oligo-nucleotide hybridization kinetics. Biochemistry 31:12055–61 [Google Scholar]
  34. Monia BP, Sasmor H, Johnston JF, Freier SM, Lesnik EA. 34.  et al. 1996. Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C-raf kinase supports an antisense mechanism of action in vivo. PNAS 93:15481–84 [Google Scholar]
  35. Lacerra G, Sierakowska H, Carestia C, Fucharoen S, Summerton J. 35.  et al. 2000. Restoration of hemoglobin A synthesis in erythroid cells from peripheral blood of thalassemic patients. PNAS 97:9591–96 [Google Scholar]
  36. Suwanmanee T, Sierakowska H, Fucharoen S, Kole R. 36.  2002. Repair of a splicing defect in erythroid cells from patients with β-thalassemia/HbE disorder. Mol. Ther. 6:718–26 [Google Scholar]
  37. Sazani P, Gemignani F, Kang SH, Maier MA, Manoharan M. 37.  et al. 2002. Systemically delivered antisense oligomers upregulate gene expression in mouse tissues. Nat. Biotechnol. 20:1228–33 [Google Scholar]
  38. La Spada AR, Paulson HL, Fischbeck KH. 38.  1994. Trinucleotide repeat expansion in neurological disease. Ann. Neurol. 36:814–22 [Google Scholar]
  39. Orr HT, Zoghbi HY. 39.  2007. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30:575–621 [Google Scholar]
  40. Ranum LP, Cooper TA. 40.  2006. RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29:259–77 [Google Scholar]
  41. Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W. 41.  et al. 2001. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:864–67 [Google Scholar]
  42. Mankodi A, Logigian E, Callahan L, McClain C, White R. 42.  et al. 2000. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289:1769–73 [Google Scholar]
  43. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M. 43.  et al. 2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–56 [Google Scholar]
  44. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S. 44.  et al. 2011. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–68 [Google Scholar]
  45. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA. 45.  et al. 1983. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306:234–38 [Google Scholar]
  46. Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M. 46.  et al. 2012. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488:111–15 [Google Scholar]
  47. Mulders SA, van den Broek WJ, Wheeler TM, Croes HJ, van Kuik-Romeijn P. 47.  et al. 2009. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. PNAS 106:13915–20 [Google Scholar]
  48. Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X. 48.  et al. 2009. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325:336–39 [Google Scholar]
  49. Hu J, Matsui M, Gagnon KT, Schwartz JC, Gabillet S. 49.  et al. 2009. Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat. Biotechnol. 27:478–84 [Google Scholar]
  50. Gagnon KT, Watts JK, Pendergraff HM, Montaillier C, Thai D. 50.  et al. 2011. Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates. J. Am. Chem. Soc. 133:8404–7 [Google Scholar]
  51. Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE. 51.  et al. 2013. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol. 126:829–44 [Google Scholar]
  52. Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL. 52.  et al. 2013. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–46 [Google Scholar]
  53. Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA. 53.  et al. 2013. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80:415–28 [Google Scholar]
  54. Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P. 54.  et al. 2013. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. PNAS 110:E4530–39 [Google Scholar]
  55. Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF. 55.  et al. 2013. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 126:385–99 [Google Scholar]
  56. May S, Hornburg D, Schludi MH, Arzberger T, Rentzsch K. 56.  et al. 2014. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 128:485–503 [Google Scholar]
  57. Mori K, Weng SM, Arzberger T, May S, Rentzsch K. 57.  et al. 2013. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–38 [Google Scholar]
  58. Turner DH, Sugimoto N, Freier SM. 58.  1988. RNA structure prediction. Annu. Rev. Biophys. Biophys. Chem. 17:167–92 [Google Scholar]
  59. Deigan KE, Li TW, Mathews DH, Weeks KM. 59.  2009. Accurate SHAPE-directed RNA structure determination. PNAS 106:97–102 [Google Scholar]
  60. Mathews DH, Disney MD, Childs JL, Schroeder SJ, Zuker M, Turner DH. 60.  2004. Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. PNAS 101:7287–92 [Google Scholar]
  61. Zuker M. 61.  2003. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31:3406–15 [Google Scholar]
  62. Woese CR, Magrum LJ, Gupta R, Siegel RB, Stahl DA. 62.  et al. 1980. Secondary structure model for bacterial 16S ribosomal RNA: phylogenetic, enzymatic and chemical evidence. Nucleic Acids Res. 8:2275–93 [Google Scholar]
  63. Gutell RR, Weiser B, Woese CR, Noller HF. 63.  1985. Comparative anatomy of 16-S-like ribosomal RNA. Prog. Nucleic Acid Res. Mol. Biol. 32:155–216 [Google Scholar]
  64. Childs-Disney JL, Wu M, Pushechnikov A, Aminova O, Disney MD. 64.  2007. A small molecule microarray platform to select RNA internal loop-ligand interactions. ACS Chem. Biol. 2:745–54 [Google Scholar]
  65. Disney MD, Labuda LP, Paul DJ, Poplawski SG, Pushechnikov A. 65.  et al. 2008. Two-dimensional combinatorial screening identifies specific aminoglycoside-RNA internal loop partners. J. Am. Chem. Soc. 130:11185–94 [Google Scholar]
  66. Auerbach T, Mermershtain I, Davidovich C, Bashan A, Belousoff M. 66.  et al. 2010. The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics. PNAS 107:1983–88 [Google Scholar]
  67. Borovinskaya MA, Pai RD, Zhang W, Schuwirth BS, Holton JM. 67.  et al. 2007. Structural basis for aminoglycoside inhibition of bacterial ribosome recycling. Nat. Struct. Mol. Biol. 14:727–32 [Google Scholar]
  68. Ippolito JA, Kanyo ZF, Wang D, Franceschi FJ, Moore PB. 68.  et al. 2008. Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit. J. Med. Chem. 51:3353–56 [Google Scholar]
  69. Moehle K, Athanassiou Z, Patora K, Davidson A, Varani G, Robinson JA. 69.  2007. Design of β-hairpin peptidomimetics that inhibit binding of α-helical HIV-1 Rev protein to the Rev response element RNA. Angew. Chem. Int. Ed. Engl. 469101–4
  70. Athanassiou Z, Patora K, Dias RL, Moehle K, Robinson JA, Varani G. 70.  2007. Structure-guided peptidomimetic design leads to nanomolar β-hairpin inhibitors of the Tat-TAR interaction of bovine immunodeficiency virus. Biochemistry 46:741–51 [Google Scholar]
  71. Leeper TC, Athanassiou Z, Dias RL, Robinson JA, Varani G. 71.  2005. TAR RNA recognition by a cyclic peptidomimetic of Tat protein. Biochemistry 44:12362–72 [Google Scholar]
  72. Davidson A, Patora-Komisarska K, Robinson JA, Varani G. 72.  2011. Essential structural requirements for specific recognition of HIV TAR RNA by peptide mimetics of Tat protein. Nucleic Acids Res. 39:248–56 [Google Scholar]
  73. Lalonde MS, Lobritz MA, Ratcliff A, Chamanian M, Athanassiou Z. 73.  et al. 2011. Inhibition of both HIV-1 reverse transcription and gene expression by a cyclic peptide that binds the Tat-transactivating response element (TAR) RNA. PLOS Pathog. 7:e1002038 [Google Scholar]
  74. Davidson A, Leeper TC, Athanassiou Z, Patora-Komisarska K, Karn J. 74.  et al. 2009. Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein. PNAS 106:11931–36 [Google Scholar]
  75. Stelzer AC, Kratz JD, Zhang Q, Al-Hashimi HM. 75.  2010. RNA dynamics by design: biasing ensembles towards the ligand-bound state. Angew. Chem. Int. Ed. Engl. 49:5731–33 [Google Scholar]
  76. Stelzer AC, Frank AT, Kratz JD, Swanson MD, Gonzalez-Hernandez MJ. 76.  et al. 2011. Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble. Nat. Chem. Biol. 7:553–59 [Google Scholar]
  77. Lee MM, Pushechnikov A, Disney MD. 77.  2009. Rational and modular design of potent ligands targeting the RNA that causes myotonic dystrophy 2. ACS Chem. Biol. 4:345–55 [Google Scholar]
  78. Childs-Disney JL, Yildirim I, Park H, Lohman JR, Guan L. 78.  et al. 2014. Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. ACS Chem. Biol. 9:538–50 [Google Scholar]
  79. Rzuczek SG, Gao Y, Tang ZZ, Thornton CA, Kodadek T, Disney MD. 79.  2013. Features of modularly assembled compounds that impart bioactivity against an RNA target. ACS Chem. Biol. 8:2312–21 [Google Scholar]
  80. Agnew HD, Rohde RD, Millward SW, Nag A, Yeo WS. 80.  et al. 2009. Iterative in situ click chemistry creates antibody-like protein-capture agents. Angew. Chem. Int. Ed. Engl. 48:4944–48 [Google Scholar]
  81. Kolb HC, Finn MG, Sharpless KB. 81.  2001. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. Engl. 40:2004–21 [Google Scholar]
  82. Lewis WG, Green LG, Grynszpan F, Radic Z, Carlier PR. 82.  et al. 2002. Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew. Chem. Int. Ed. Engl. 41:1053–57 [Google Scholar]
  83. Millward SW, Henning RK, Kwong GA, Pitram S, Agnew HD. 83.  et al. 2011. Iterative in situ click chemistry assembles a branched capture agent and allosteric inhibitor for Akt1. J. Am. Chem. Soc. 133:18280–88 [Google Scholar]
  84. Rzuczek SG, Park H, Disney MD. 84.  2014. A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Angew. Chem. Int. Ed. Engl. 53:10956–59 [Google Scholar]
  85. Stern S, Moazed D, Noller HF. 85.  1988. Structural analysis of RNA using chemical and enzymatic probing monitored by primer extension. Methods Enzymol. 164:481–89 [Google Scholar]
  86. Moazed D, Noller HF. 86.  1987. Interaction of antibiotics with functional sites in 16S ribosomal RNA. Nature 327:389–94 [Google Scholar]
  87. Regulski EE, Breaker RR. 87.  2008. In-line probing analysis of riboswitches. Methods Mol. Biol. 419:53–67 [Google Scholar]
  88. Lomenick B, Olsen RW, Huang J. 88.  2011. Identification of direct protein targets of small molecules. ACS Chem. Biol. 6:34–46 [Google Scholar]
  89. Liang FS, Greenberg WA, Hammond JA, Hoffmann J, Head SR, Wong CH. 89.  2006. Evaluation of RNA-binding specificity of aminoglycosides with DNA microarrays. PNAS 103:12311–16 [Google Scholar]
  90. Rijal K, Bao X, Chow CS. 90.  2014. Amino acid-linked platinum(II) analogues have altered specificity for RNA compared to cisplatin. Chem. Commun. 50:3918–20 [Google Scholar]
  91. Rijal K, Chow CS. 91.  2008. A new role for cisplatin: probing ribosomal RNA structure. Chem. Commun. 1:107–9 [Google Scholar]
  92. Hostetter AA, Osborn MF, DeRose VJ. 92.  2012. RNA-Pt adducts following cisplatin treatment of Saccharomyces cerevisiae. ACS Chem. Biol. 7:218–25 [Google Scholar]
  93. Moghaddam AD, White JD, Cunningham RM, Loes AN, Haley MM, DeRose VJ. 93.  2015. Convenient detection of metal-DNA, metal-RNA, and metal-protein adducts with a click-modified Pt(II) complex. Dalton Trans. 44:3536–39 [Google Scholar]
  94. Osborn MF, White JD, Haley MM, DeRose VJ. 94.  2014. Platinum-RNA modifications following drug treatment in S. cerevisiae identified by click chemistry and enzymatic mapping. ACS Chem. Biol. 9:2404–11 [Google Scholar]
  95. White JD, Osborn MF, Moghaddam AD, Guzman LE, Haley MM, DeRose VJ. 95.  2013. Picazoplatin, an azide-containing platinum(II) derivative for target analysis by click chemistry. J. Am. Chem. Soc. 135:11680–83 [Google Scholar]
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Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells
Annual Review of Pharmacology and Toxicology 56, 123 (2016); https://doi.org/10.1146/annurev-pharmtox-010715-103910
/content/journals/10.1146/annurev-pharmtox-010715-103910
/content/journals/10.1146/annurev-pharmtox-010715-103910
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