Approaches for the Discovery of Small Molecule Ligands Targeting microRNAs

  • Daniel A. Lorenz
  • Amanda L. GarnerEmail author
Part of the Topics in Medicinal Chemistry book series (TMC, volume 27)


RNA is essential for life, serving as the intermediate between genomic storage and protein function. As our knowledge of biological systems has grown, so has our understanding of RNA, revealing additional functions of this critical class of biomolecules. One class of RNA, microRNAs (miRNA), highlights the fundamental role of non-coding RNA in higher organisms. miRNAs regulate nearly every biological pathway through targeted translational suppression, and dysregulation of miRNA expression has been implicated in many human disease states. Thus, therapeutically targeting miRNAs with small molecule ligands is of growing importance. Herein we focus on methods employed to discover small molecule miRNA ligands, their successes thus far, and future directions for the field.


High-throughput screening microRNAs Small molecules Therapeutics 


  1. 1.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefGoogle Scholar
  2. 2.
    Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75:855–862CrossRefGoogle Scholar
  3. 3.
    Ruvkun G, Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906CrossRefGoogle Scholar
  4. 4.
    Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408:86–89CrossRefGoogle Scholar
  5. 5.
    Friedman RC, Kai-How Farh K, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105CrossRefGoogle Scholar
  6. 6.
    Li Z, Rana TM (2014) Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 13:622–638CrossRefGoogle Scholar
  7. 7.
    Roush S, Slack FJ (2008) The let-7 family of microRNAs. Trends Cell Biol 18:505–516CrossRefGoogle Scholar
  8. 8.
    Han C, Yu Z, Duan Z, Kan Q (2014) Role of microRNA-1 in human cancer and its therapeutic potentials. Biomed Res Int 2014:428371Google Scholar
  9. 9.
    Ma L (2010) Role of miR-10b in breast cancer metastasis. Breast Cancer Res 12:210CrossRefGoogle Scholar
  10. 10.
    Pfeffer S, Yang CH, Pfeffer LM (2015) The role of miR-21 in cancer. Drug Dev Res 76:270–277CrossRefGoogle Scholar
  11. 11.
    Chhabra R, Dubey R, Saini N (2010) Cooperative and individualistic functions of the microRNAs in the miR-23a-27a-24-2 cluster and its implications in human diseases. Mol Cancer 9:232CrossRefGoogle Scholar
  12. 12.
    Wang Y, Zhang X, Li H, Yu J, Ren X (2013) The role of miRNA-29 family in cancer. Eur J Cell Biol 92:123–128CrossRefGoogle Scholar
  13. 13.
    Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199CrossRefGoogle Scholar
  14. 14.
    Guttilla IK, White BA (2009) Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J Biol Chem 284:23204–23216CrossRefGoogle Scholar
  15. 15.
    Henke JI, Goergen D, Zheng J, Song Y, Schuttler CG, Fehr C, Junemann C, Niepmann M (2008) microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J 27:3300–3310CrossRefGoogle Scholar
  16. 16.
    Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu C-G, Calin GA, Giovannini C, Ferrazzi M, Grazi GL, Croce CM, Bolondi L, Negrini M (2007) Cyclin G1 is a target of miR-122, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 67:6092–6099CrossRefGoogle Scholar
  17. 17.
    Ozen M, Creighton CJ, Ozdemir M, Ittmann M (2008) Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 27:1788–1793CrossRefGoogle Scholar
  18. 18.
    Thum T, Catalucci D, Bauersachs J (2008) MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res 79:562–570CrossRefGoogle Scholar
  19. 19.
    Isobe T, Hisamori S, Hogan DJ, Zabala M, Hendrickson DG, Dalerba P, Cai S, Scheeren F, Kuo AH, Sikandar SS, Lam JS, Qian D, Dirbas FM, Somlo G, Lao K, Brown PO, Clarke MF, Shimono Y (2014) miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Elife 3:e01977CrossRefGoogle Scholar
  20. 20.
    Faraoni I, Antonetti FR, Cardone J, Bonmassar E (2009) miR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta 1792:497–505CrossRefGoogle Scholar
  21. 21.
    Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL, Bassel-Duby R, Sanes JR, Olson EN (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326:1549–1554CrossRefGoogle Scholar
  22. 22.
    Scarola M, Schoeftner S, Schneider C, Benetti R (2010) miR-335 directly targets Rb1 (pRb/P105) in a proximal connection to P53-dependent stress response. Cancer Res 70:6925–6933CrossRefGoogle Scholar
  23. 23.
    Staedel C, Varon C, Nguyen PH, Vialet B, Chambonnier L, Rousseau B, Soubeyran I, Evrary S, Couillaud F, Darfeuille F (2015) Inhibition of gastric tumor cell growth using seed-targeting LNA as specific, long-lasting microRNA inhibitors. Mol Ther Nucleic Acids 4:e246CrossRefGoogle Scholar
  24. 24.
    Hu W, Chan CS, Wu R, Zhang C, Sun Y, Song JS, Tang LH, Levine AJ, Feng Z (2010) Negative regulation of tumor suppressor P53 by microRNA miR-504. Mol Cell 38:689–699CrossRefGoogle Scholar
  25. 25.
    Pang F, Zha R, Zhao Y, Wang Q, Chen D, Zhang Z, Chen T, Yao M, Gu J, He X (2014) MiR-525-3p enhances the migration and invasion of liver cancer cells by downregulating ZNF395. PLoS One 9:e90867CrossRefGoogle Scholar
  26. 26.
    Haga CL, Velagapudi SP, Strivelli JR, Yang W-Y, Disney MD, Phinney DG (2015) Small molecule inhibition of miR-544 biogenesis disrupts adaptive responses to hypoxia by modulating ATM-mTOR signaling. ACS Chem Biol 10:2267–2276CrossRefGoogle Scholar
  27. 27.
    Lin S, Gregory RI (2015) MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15:321–333CrossRefGoogle Scholar
  28. 28.
    Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15:509–524CrossRefGoogle Scholar
  29. 29.
    Mack GS (2007) MicroRNA gets down to business. Nat Biotechnol 25:631–638CrossRefGoogle Scholar
  30. 30.
    Wang V, Wu W (2009) MicroRNA-based therapeutics for cancer. BioDrugs 23:15–23CrossRefGoogle Scholar
  31. 31.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimuzu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 101:2999–3004CrossRefGoogle Scholar
  32. 32.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838CrossRefGoogle Scholar
  33. 33.
    Ling H, Fabbri M, Calin GA (2013) MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12:847–865CrossRefGoogle Scholar
  34. 34.
    Franceschini A, Meier R, Casanova A, Kreibich S, Daga N, Andritschke D, Dilling S, Ramo P, Emmenlauer M, Kaufmann A, Conde-Alvarez R, Low SH, Pelkmans L, Helenius A, Hardt W-D, Dehio C, von Mering C (2014) Specific inhibition of diverse pathogens in human cells by synthetic microRNA-like oligonucleotides inferred from RNAi screens. Proc Natl Acad Sci U S A 111:4548–4553CrossRefGoogle Scholar
  35. 35.
    White PJ, Anastasopoulos F, Pouton CW, Boyd BJ (2009) Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides. Expert Rev Mol Med 11:e10CrossRefGoogle Scholar
  36. 36.
    Thomas JR, Hergenrother PJ (2008) Targeting RNA with small molecules. Chem Rev 108:1171–1224CrossRefGoogle Scholar
  37. 37.
    Guan L, Disney MD (2012) Recent advances in developing small molecules targeting RNA. ACS Chem Biol 7:73–86CrossRefGoogle Scholar
  38. 38.
    Connelly CM, Moon MH, Schneekloth Jr JS (2016) The emerging role of RNA as a therapeutic target for small molecules. Cell Chem Biol 23:1077–1090CrossRefGoogle Scholar
  39. 39.
    Disney MD (2013) Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts. Drug Discov Today 18:1228–1236CrossRefGoogle Scholar
  40. 40.
    Werstuck G, Green MR (1998) Controlling gene expression in living cells through small molecule-RNA interactions. Science 282:296–298CrossRefGoogle Scholar
  41. 41.
    Sparano BA, Koide K (2007) Fluorescent sensors for specific RNA: a general paradigm using chemistry and combinatorial biology. J Am Chem Soc 129:4785–4794CrossRefGoogle Scholar
  42. 42.
    Paige JS, Wu KY, Jaffrey SR (2011) RNA mimics of green fluorescent protein. Science 333:642–646CrossRefGoogle Scholar
  43. 43.
    Serganov A, Nudler E (2013) A decade of riboswitches. Cell 152:17–24CrossRefGoogle Scholar
  44. 44.
    Terasaka N, Futai K, Katoh T, Suga H (2016) A human microRNA precursor binding to folic acid discovered by small RNA transcriptomic SELEX. RNA 22:1918–1928Google Scholar
  45. 45.
    Connelly CM, Thomas M, Deiters A (2012) High-throughput luciferase reporter assay for small-molecule inhibitors of microRNA function. J Biomol Screen 17:822–828CrossRefGoogle Scholar
  46. 46.
    Connelly CM, Deiters A (2014) Cellular microRNA sensors based on luciferase reporters. Methods Mol Biol 1095:135–146CrossRefGoogle Scholar
  47. 47.
    Connelly CM, Deiters A (2014) Identification of inhibitors of microRNA function from small molecule screens. Methods Mol Biol 1095:147–156CrossRefGoogle Scholar
  48. 48.
    Gumireddy K, Young DD, Xiong X, Hogenesch JB, Huang Q, Deiters A (2008) Small-molecule inhibitors of microRNA miR-21 function. Angew Chem Int Ed 47:7482–7484CrossRefGoogle Scholar
  49. 49.
    Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 103:2257–2261CrossRefGoogle Scholar
  50. 50.
    Selcuklu SD, Donoghue MTA, Spillane C (2009) miR-21 as a key regulator of oncogenic processes. Biochem Soc Trans 37:918–925CrossRefGoogle Scholar
  51. 51.
    Krichevsky AM, Gabriely G (2009) miR-21: a small multi-faceted RNA. J Cell Mol Med 13:39–53CrossRefGoogle Scholar
  52. 52.
    Jazbutyte V, Thum T (2010) MicroRNA-21: from cancer to cardiovascular disease. Curr Drug Targets 11:926–935CrossRefGoogle Scholar
  53. 53.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6:259–269CrossRefGoogle Scholar
  54. 54.
    Medina PP, Nolde M, Slack FJ (2010) OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467:86–90CrossRefGoogle Scholar
  55. 55.
    Cheng CJ, Slack FJ (2012) The duality of oncomiR addiction in the maintenance and treatment of cancer. Cancer J 18:232–237CrossRefGoogle Scholar
  56. 56.
    Jiang C-S, Wang X-M, Zhang S-Q, Meng L-S, Zhu W-H, Xu J, Lu S-M (2015) Discovery of 4-benzoylamino-N-(prop-2-yn-1-yl)benzamides as novel microRNA-21 inhibitors. Bioorg Med Chem 23:6510–6519CrossRefGoogle Scholar
  57. 57.
    Naro Y, Thomas M, Stephens MD, Connelly CM, Deiters A (2015) Aryl amide small-molecule inhibitors of microRNA miR-21 function. Bioorg Med Chem Lett 25:4793–4796CrossRefGoogle Scholar
  58. 58.
    Young DD, Connelly CM, Grohmann C, Deiters A (2010) Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J Am Chem Soc 132:7976–7981CrossRefGoogle Scholar
  59. 59.
    Jopling CL, Yi M-K, Lancaster AM, Lemon SM, Sarnow P (2005) Modulation of hepatits C virus RNA abundance by a liver-specific microRNA. Science 309:1577–1581CrossRefGoogle Scholar
  60. 60.
    Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Orum H (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatits C virus infection. Science 327:198–201CrossRefGoogle Scholar
  61. 61.
    Janssen HLA, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patrick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368:1685–1694CrossRefGoogle Scholar
  62. 62.
    van der Ree MH, van der Meer AJ, de Bruijne J, Maan R, van Vliet A, Welzel TM, Zeuzem S, Lawitz EJ, Rodriguez-Torres M, Kupcova V, Wiercinska-Drapalo A, Hodges MR, Janssen HLA, Reesink HW (2014) Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients. Antivir Res 111:53–59CrossRefGoogle Scholar
  63. 63.
    Ottosen S, Parsley TB, Yang L, Zeh K, van Doom L-J, van der Veer E, Raney AK, Hodges MR, Patrick AK (2014) In vitro antiviral activity and preclinical and clincal resistance profile of miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122. Antimicrob Agents Chemother 59:599–608CrossRefGoogle Scholar
  64. 64.
    van der Ree MH, van der Meer AJ, van Nuenen AC, de Bruijne J, Ottosen S, Janssen HLA, Kootstra NA, Reesink HW (2015) Miravirsen dosing in chronic hepatits C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma. Aliment Pharmacol Ther 43:102–113Google Scholar
  65. 65.
    Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D, Bader AG (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res 70:5923–5930CrossRefGoogle Scholar
  66. 66.
    Adams BD, Parsons C, Slack FJ (2016) The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas. Expert Opin Ther Targets 20:737–753CrossRefGoogle Scholar
  67. 67.
    Daige CL, Wiggins JF, Priddy L, Nelligan-Davis T, Zhao J, Brown D (2014) Systemic delivery of a miR-34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 13:2352–2360CrossRefGoogle Scholar
  68. 68.
    Xiao Z, Li CH, Chan SL, Xu F, Feng L, Wang Y, Jiang JD, Sung JJY, Cheng CHK, Chen Y (2014) A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma. Cancer Res 74:6236–6247CrossRefGoogle Scholar
  69. 69.
    Tan S-B, Huang C, Chen X, Wu Y, Zhou M, Zhang C, Zhang Y (2013) Small molecular inhibitors of miR-1 identified from photocycloadducts of acetylenes with 2-methoxy-1,4-napthalenequinone. Bioorg Med Chem 21:6124–6131CrossRefGoogle Scholar
  70. 70.
    Tan S-B, Li J, Chen X, Zhang W, Zhang D, Zhang C, Li D, Zhang Y (2014) Small molecule inhibitor of myogenic microRNAs leads to a discovery of miR-221/222-myoD-myomiRs regulatory pathway. Chem Biol 21:1265–1270CrossRefGoogle Scholar
  71. 71.
    Chen X, Huang C, Zhang W, Wu Y, Chen X, Zhang C-Y, Zhang Y (2012) A universal activator of microRNAs identified from photoreaction products. Chem Commun 48:6432–6433CrossRefGoogle Scholar
  72. 72.
    Shan G, Li Y, Zhang J, Li W, Szulwach KE, Duan R, Faghihi MA, Khalil AM, Lu L, Paroo Z, Chan AWS, Shi Z, Liu Q, Wahlestedt C, He C, Jin P (2008) A small molecule enhances RNA interference and promotes microRNA processing. Nat Biotechnol 26:933–940CrossRefGoogle Scholar
  73. 73.
    Melo S, Villanueva A, Moutinho C (2011) Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing. Proc Natl Acad Sci U S A 108:4394–4300CrossRefGoogle Scholar
  74. 74.
    Shum D, Bhinder B, Radu C, Farazi T, Landthaler M, Tuschl T, Calder P, Ramirez CN, Djaballah H (2012) An image-based biosensor assay strategy to screen for modulators of the microRNA 21 biogenesis pathway. Comb Chem High Throughput Screen 15:529–541CrossRefGoogle Scholar
  75. 75.
    Watashi K, Yeung ML, Starost MF, Hosmane RS, Jeang K-T (2010) Identification of small molecules that suppress microRNA function and reverse tumorigenesis. J Biol Chem 285:24707–24716CrossRefGoogle Scholar
  76. 76.
    Bose D, Jayaraj G, Suryawanshi H, Agarwala P, Pore SK, Banerjee R, Maiti S (2012) The tuberculosis drug streptomycin as a potential cancer therapeutic: inhibition of miR-21 function by directly targeting its precursor. Angew Chem Int Ed 51:1019–1023CrossRefGoogle Scholar
  77. 77.
    Lorenz DA, Song JM, Garner AL (2015) High-throughput platform assay technology for the discovery of pre-microRNA-selective small molecule probes. Bioconjug Chem 26:19–23CrossRefGoogle Scholar
  78. 78.
    Tran TPA, Vo DD, Di Giorgio A, Duca M (2015) Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: old scaffolds for new perspectives in RNA targeting. Bioorg Med Chem 23:5334–5344CrossRefGoogle Scholar
  79. 79.
    Nahar S, Ranjan N, Ray A, Arya DP, Maiti S (2015) Potent inhibition of miR-27a by neomycin-benzimidazole conjugates. Chem Sci 6:5837–5846CrossRefGoogle Scholar
  80. 80.
    Bose D, Jayaraj GG, Kumar S, Maiti S (2013) A molecule-beacon-based screen for small molecule inhibitors of miRNA maturation. ACS Chem Biol 8:930–938CrossRefGoogle Scholar
  81. 81.
    MacBeath G, Koehler AN, Schreiber SL (1999) Printing small molecule as microarrays and detecting protein-ligand interactions en mass. J Am Chem Soc 121:7967–7968CrossRefGoogle Scholar
  82. 82.
    Hong JA, Neel DV, Wassaf D, Caballero F, Koehler AN (2014) Recent discoveries and applications involving small-molecule microarrays. Curr Opin Chem Biol 18:21–28CrossRefGoogle Scholar
  83. 83.
    Abulwerdi FA, Schneekloth Jr JS (2016) Microarray-based technologies for the discovery of selective, RNA-binding molecules. Methods 103:188–195CrossRefGoogle Scholar
  84. 84.
    Connelly CM, Boer RE, Moon MH, Gareiss P, Schneekloth JS Jr (2017) Discovery of inhibitors of microRNA-21 processing using small molecule microarrays. ACS Chem Biol 12:435–443CrossRefGoogle Scholar
  85. 85.
    Chirayil S, Chirayil R, Luebke KJ (2009) Discovering ligands for a microRNA precursor with peptoid microarrays. Nucleic Acids Res 37:5486–5497CrossRefGoogle Scholar
  86. 86.
    Chirayil R, Wu Q, Amezcua C, Luebke KJ (2014) NMR characterization of an oligonucleotide model of the MiR-21 pre-element. PLoS One 9:e108231CrossRefGoogle Scholar
  87. 87.
    Diaz JP, Chirayil R, Chirayil S, Tom M, Head KJ, Luebke KJ (2014) Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha. RNA 20:528–539CrossRefGoogle Scholar
  88. 88.
    Carlson CB, Beal PA (2002) Points of attachment and sequence of immobilized peptide-acridine conjugates control affinity for nucleic acids. J Am Chem Soc 124:8510–8511CrossRefGoogle Scholar
  89. 89.
    Disney MD, Seeberger PH (2004) Aminoglycoside microarray to explore interactions of antibiotics with RNAs and proteins. Chem Eur J 10:3308–3314CrossRefGoogle Scholar
  90. 90.
    Pai J, Hyun S, Hyun JY, Park S-H, Kim W-J, Bae S-H, Kim N-K, Yu J, Shin I (2016) Screening of pre-miRNA-155 binding peptides for apoptosis inducing activity using peptide microarrays. J Am Chem Soc 138:857–867CrossRefGoogle Scholar
  91. 91.
    Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, Lund E, Dahlberg JE (2005) Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A 102:3627–3632CrossRefGoogle Scholar
  92. 92.
    Hyun S, Han A, Jo MH, Hohng S, Yu J (2014) Dicer nuclease-promoted production of Let7a-1 microRNA is enhanced in the presence of tryptophan-containing amphiphilic peptides. Chembiochem 15:1651–1659CrossRefGoogle Scholar
  93. 93.
    Bose D, Nahar S, Rai MK, Ray A, Chakraborty K, Maiti S (2010) Selective inhibition of miR-21 by phage display screened peptide. Nucleic Acids Res 43:4342–4352CrossRefGoogle Scholar
  94. 94.
    Nahar S, Bose D, Pal S, Chakraborty TK, Maiti S (2015) Cyclic cationic peptides containing sugar amino acids selectively distinguishes and inhibits maturation of pre-miRNAs of the same family. Nucleic Acid Ther 25:323–329CrossRefGoogle Scholar
  95. 95.
    Krishnamurthy M, Simon K, Orendt AM, Beal PA (2007) Macrocyclic helix-threading peptides for targeting RNA. Angew Chem Int Ed 46:7044–7047CrossRefGoogle Scholar
  96. 96.
    Chen Y, Yang F, Zubovic L, Pavelitz T, Yang W, Godin K, Walker M, Zheng S, Macchi P, Varani G (2016) Targeting inhibition of oncogenic miR-21 maturation with designed RNA-binding proteins. Nat Chem Biol 12:717–723CrossRefGoogle Scholar
  97. 97.
    Velagapudi SP, Disney MD (2014) Two-dimensional combinatorial screening enables the bottom-up design of a microRNA-10b inhibitor. Chem Commun 50:3027–3029CrossRefGoogle Scholar
  98. 98.
    Disney MD, Labuda LP, Paul DJ, Poplawski SG, Pushechnikov A, Tran T, Velagapudi SP, Wu M, Childs-Disney JL (2008) Two-dimensional combinatorial screening identifies specific aminoglycoside-RNA internal loop partners. J Am Chem Soc 130:11185–11194CrossRefGoogle Scholar
  99. 99.
    Velagapudi SP, Seedhouse SJ, Disney MD (2010) Structure-activity relationships through sequencing (StARTS) defines optimal and suboptimal RNA motif targets for small molecules. Angew Chem Int Ed 49:3816–3818CrossRefGoogle Scholar
  100. 100.
    Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449:682–687CrossRefGoogle Scholar
  101. 101.
    Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson EG, Teruya-Feldstein J, Bell GW, Weinberg RA (2010) Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol 28:341–347CrossRefGoogle Scholar
  102. 102.
    Davies BP, Arenz C (2006) A homogeneous assay for microRNA maturation. Angew Chem Int Ed 45:5550–5552CrossRefGoogle Scholar
  103. 103.
    Davies BP, Arenz C (2008) A fluorescence probe for assaying microRNA maturation. Bioorg Med Chem 16:49–55CrossRefGoogle Scholar
  104. 104.
    Vo DD, Staedel C, Zehnacker L, Benhida R, Darfeuille F, Duca M (2014) Targeting the production of oncogenic microRNAs with multimodal synthetic small molecules. ACS Chem Biol 9:711–721CrossRefGoogle Scholar
  105. 105.
    Comley J (2003) Assay interference a limiting factor in HTS? Drug Discov World 4:91–98Google Scholar
  106. 106.
    Imbert P-E, Unterreiner V, Siebert D, Gubler H, Parker C, Gabriel D (2007) Recommendations for the reduction of compound artifacts in time-resolved fluorescence resonance energy transfer assays. Assay Drug Dev Technol 5:363–372CrossRefGoogle Scholar
  107. 107.
    MacRae IJ, Zhou Z, Doudna JA (2007) Structural determinants of RNA recognition and cleavage by Dicer. Nat Struct Mol Biol 14:934–940CrossRefGoogle Scholar
  108. 108.
    Feng Y, Zhang X, Graves P, Zeng Y (2012) A comprehensive analysis of precursor microRNA cleavage by human Dicer. RNA 18:2083–2092CrossRefGoogle Scholar
  109. 109.
    Klemm CM, Berthelmann A, Neubacher S, Arenz C (2009) Short and efficient synthesis of alkyne-modified amino glycoside building blocks. Eur J Org Chem 17:2788–2794CrossRefGoogle Scholar
  110. 110.
    Vo DD, Tran TPA, Staedel C, Benhida R, Darfeuille F, Di Giorgio A, Duca M (2016) Oncogenic microRNAs biogenesis as a drug target: structure-activity relationship studies on new aminoglycoside conjugates. Chemistry 22:5350–5362CrossRefGoogle Scholar
  111. 111.
    Judson RL, Babiarz JE, Venere M, Blelloch R (2009) Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 27:459–461CrossRefGoogle Scholar
  112. 112.
    Wang Y, Blelloch R (2009) Cell cycle regulation by microRNAs in embryonic stem cells. Cancer Res 69:4093–4096CrossRefGoogle Scholar
  113. 113.
    Podolska K, Sedlak D, Bartunek P, Svoboda P (2014) Fluorescence-based high-throughput screening of Dicer cleavage activity. J Biomol Screen 19:417–426CrossRefGoogle Scholar
  114. 114.
    Tran T, Disney MD (2012) Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations. Nat Commun 3:1125CrossRefGoogle Scholar
  115. 115.
    Zhang J, Umemoto S, Nakatani K (2010) Fluorescent indicator displacement assay for ligand-RNA interactions. J Am Chem Soc 132:3660–3661CrossRefGoogle Scholar
  116. 116.
    Maiti M, Nauwelaerts K, Herdewijn P (2012) Pre-microRNA binding aminoglycosides and antitumor drugs as inhibitors of Dicer catalyzed microRNA processing. Bioorg Med Chem Lett 22:1709–1711CrossRefGoogle Scholar
  117. 117.
    Murata A, Fukuzumi T, Umemoto S, Nakatani K (2013) Xanthone derivatives as potential inhibitors of miRNA processing by human Dicer: targeting secondary structures of pre-miRNA by small molecules. Bioorg Med Chem Lett 23:252–255CrossRefGoogle Scholar
  118. 118.
    Murata A, Harada Y, Fukuzumi T, Nakatani K (2013) Fluorescent indicator displacement assay of ligands targeting 10 microRNA precursors. Bioorg Med Chem 21:7101–7106CrossRefGoogle Scholar
  119. 119.
    Fukuzumi T, Murata A, Aikawa H, Harada Y, Nakatani K (2015) Exploratory study on the RNA-binding structural motifs by library screening targeting pre-miR-29a. Chemistry 21:16859–16867CrossRefGoogle Scholar
  120. 120.
    Murata A, Otabe T, Zhang J, Nakatani K (2016) BZDANP, a small-molecule modulator of pre-miR-29a maturation by Dicer. ACS Chem Biol 11:2790–2796CrossRefGoogle Scholar
  121. 121.
    Watkins D, Jiang L, Nahar S, Maiti S, Arya DP (2015) A pH sensitive high-throughput assay for miRNA binding of a peptide-aminoglycoside (PA) library. PLoS One 10:e0144251CrossRefGoogle Scholar
  122. 122.
    Lorenz DA, Garner AL (2016) A click chemistry-based microRNA maturation assay optimized for high-throughput screening. Chem Commun 52:8267–8270CrossRefGoogle Scholar
  123. 123.
    Garner AL, Janda KD (2010) cat-ELCCA: a robust method to monitor the fatty acid acyltransferase activity of ghrelin O-acyltransferase (GOAT). Angew Chem Int Ed 49:9630–9634CrossRefGoogle Scholar
  124. 124.
    Garner AL, Janda KD (2011) A small molecule antagonist of ghrelin O-acyltransferase (GOAT). Chem Commun 47:7512–7514CrossRefGoogle Scholar
  125. 125.
    Zhang J-H, Chung TDY, Oldenburg KR (1999) A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4:67–73CrossRefGoogle Scholar
  126. 126.
    Mustoe AM, Brooks III CL, Al-Hashimi HM (2014) Hierarchy of RNA functional dynamics. Annu Rev Biochem 83:441–466CrossRefGoogle Scholar
  127. 127.
    Turner DH, Sugimoto N, Freier SM (1988) RNA structure prediction. Annu Rev Biophys Biophys Chem 17:167–192CrossRefGoogle Scholar
  128. 128.
    Parisien M, Major F (2008) The MC-Fold and MC-Sym pipeline infers RNA structure from sequence data. Nature 452:51–55CrossRefGoogle Scholar
  129. 129.
    Disney MD, Winkelsas AM, Velagapudi SP, Southern M, Fallahi M, Childs-Disney JL (2016) Inforna 2.0: a platform for the sequence-based design of small molecules targeting structured RNAs. ACS Chem Biol 11:1720–1728CrossRefGoogle Scholar
  130. 130.
    Velagapudi SP, Gallo SM, Disney MD (2014) Sequence-based design of bioactive small molecules that target precursor microRNAs. Nat Chem Biol 10:291–297CrossRefGoogle Scholar
  131. 131.
    Liu B, Childs-Disney JL, Znosko BM, Wang D, Fallahi M, Gallo SM, Disney MD (2016) Analysis of secondary structural elements in human microRNA hairpin precursors. BMC Bioinformatics 17:112CrossRefGoogle Scholar
  132. 132.
    Jamal S, Periwal V, Consortium OSDD, Scaria V (2012) Computational analysis and predictive modeling of small molecule modulators of microRNA. J Cheminform 4:16CrossRefGoogle Scholar
  133. 133.
    Wehler T, Brenk R (2017) Structure-based discovery of small molecules binding to RNA. Topics Med Chem. doi: 10.1007/7355_2016_29
  134. 134.
    Shi Z, Zhang J, Qian X, Han L, Zhang K, Chen L, Liu J, Ren Y, Yang M, Zhang A, Pu P, Kang C (2013) AC1MMYR2, an inhibitor of Dicer-mediated biogenesis of oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression. Cancer Res 73:5519–5531CrossRefGoogle Scholar
  135. 135.
    Ren Y, Zhou X, Liu X, Jia H-H, Zhao X-H, Wang Q-X, Han L, Song X, Zhu Z-Y, Sun T, Jiao H-X, Tian W-P, Yang Y-Q, Zhao X-L, Zhang L, Mei M, Kang C-S (2016) Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy. Cancer Lett 374:96–106CrossRefGoogle Scholar
  136. 136.
    Childs-Disney JL, Wu M, Pushechnikov A, Aminova O, Disney MD (2007) A small molecule microarray platform to select RNA internal loop-ligand interactions. ACS Chem Biol 2:745–754CrossRefGoogle Scholar
  137. 137.
    Velagapudi SP, Seedhouse SJ, French J, Disney MD (2011) Defining the RNA internal loops preferred by benzimidazole derivatives via 2D combinatorial screening and computational analysis. J Am Chem Soc 133:10111–10118CrossRefGoogle Scholar
  138. 138.
    Disney MD, Angelbello AJ (2016) Rational design of small molecules targeting oncogenic noncoding RNAs from sequence. Acc Chem Res 49:2698–2704CrossRefGoogle Scholar
  139. 139.
    Costales MG, Childs-Disney JL, Disney MD (2017) Computational tools for design of selective small molecules targeting RNA: from small molecule microarray to chemical similarity searching. Topics Med Chem. doi: 10.1007/7355_2016_21
  140. 140.
    Dambal S, Shah M, Mihelich B, Nonn L (2015) The microRNA-183 cluster: the family that plays together stay together. Nucleic Acids Res 43:7173–7188CrossRefGoogle Scholar
  141. 141.
    Costales MG, Rzuczek SG, Disney MD (2016) Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA. Bioorg Med Chem Lett 26:2605–2609CrossRefGoogle Scholar
  142. 142.
    Velagapudi SP, Cameron MD, Haga CL, Rosenberg LH, Lafitte M, Duckett DR, Phinney DG, Disney MD (2016) Design of a small molecule against an oncogenic noncoding RNA. Proc Natl Acad Sci U S A 113:5898–5903CrossRefGoogle Scholar
  143. 143.
    Haga CL, Phinney DG (2012) MicroRNAs in the imprinted DLK1-DIO3 region repress the epithelial-to-mesenchymal transition by targeting the TWIST1 protein signaling network. J Biol Chem 287:42695–42707CrossRefGoogle Scholar
  144. 144.
    Childs-Disney JL, Disney MD (2016) Small molecule targeting of a microRNA associated with hepatocellular carcinoma. ACS Chem Biol 11:375–380CrossRefGoogle Scholar
  145. 145.
    Mei H-Y, Mack DP, Galan AA, Halim NS, Heldsinger A, Loo JA, Moreland DW, Sannes-Lowery KA, Sharmeen L, Truong HN, Czarnik AW (1997) Discovery of selective, small-molecule inhibitors of RNA complexes – I. The Tat protein/TAR RNA complexes required for HIV-1 transcription. Bioorg Med Chem 5:1173–1184CrossRefGoogle Scholar
  146. 146.
    Mei H-Y, Cui M, Heldsinger A, Lemrow SM, Loo JA, Sannes-Lowery KA, Sharmeen L, Czarnik AW (1998) Inhibitors of protein-RNA complexation that target RNA: specific recognition of human immunodeficiency virus type 1 TAR RNA by small organic molecules. Biochemistry 37:14204–14212CrossRefGoogle Scholar
  147. 147.
    Stelzer AC, Frank AT, Kratz JD, Swanson MD, Gonzalez-Hernandez MJ, Lee J, Andricioaei I, Markovitz DM, Al-Hashimi HM (2011) Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble. Nat Chem Biol 7:553–559CrossRefGoogle Scholar
  148. 148.
    Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z, Ling KKY, Karp GM, Qi H, Woll MG, Chen G, Zhang N, Gabbeta V, Vazirani P, Bhattacharyya A, Furia B, Risher N, Sheedy J, Kong R, Ma J, Turpoff A, Lee C-S, Zhang X, Moon Y-C, Trifillis P, Welch EM, Colacino JM, Babiak J, Almstead NG, Peltz SW, Eng LA, Chen KS, Mull JL, Lynes MS, Rubin LL, Fontoura P, Santarelli L, Haehnke D, McCarthy KD, Schmucki R, Ebeling M, Sivaramakrishnan M, Ko C-P, Paushkin SV, Ratni H, Gerlach I, Ghosh A, Metzger F (2014) Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345:688–693CrossRefGoogle Scholar
  149. 149.
    Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, Sivasankaran R (2015) SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol 11:511–517CrossRefGoogle Scholar
  150. 150.
    Tan GS, Chiu C-H, Garchow BG, Metzler D, Diamond SL, Kiriakidou M (2012) Small molecule inhibition of RISC loading. ACS Chem Biol 7:403–410CrossRefGoogle Scholar
  151. 151.
    Schmidt MF, Korb O, Abell C (2013) MicroRNA-specific Argonaute 2 protein inhibitors. ACS Chem Biol 8:2122–2126CrossRefGoogle Scholar
  152. 152.
    Masciarelli S, Quaranta R, Iosue I, Colotti G, Padula F, Varchi G, Fazi F, Del Rio A (2014) A small-molecule targeting the microRNA binding domain of Argonaute 2 improves the retinoic acid differentiation response of the acute promyelocytic leukemia cell line NB4. ACS Chem Biol 9:1674–1679CrossRefGoogle Scholar
  153. 153.
    Hesse M, Arenz C (2016) A rapid and versatile assay for Ago2-mediated cleavage by using branched rolling circle amplification. Chembiochem 17:304–307CrossRefGoogle Scholar
  154. 154.
    Lin S, Gregory RI (2015) Identification of small molecule inhibitors of Zcchc11 TUTase activity. RNA Biol 12:792–800CrossRefGoogle Scholar
  155. 155.
    Roos M, Pradere U, Ngondo RP, Behera A, Allegrini S, Civenni G, Zagalak JA, Marchand J-R, Menzi M, Towbin H, Scheuermann J, Neri D, Caflisch A, Catapano CV, Claudo C, Hall J (2016) A small-molecule inhibitor of Lin28. ACS Chem Biol 11:2773–2781CrossRefGoogle Scholar
  156. 156.
    Lightfoot HL, Miska EA, Balasubramanian S (2016) Identification of small molecule inhibitors of the Lin28-mediated blockage of pre-let-7g processing. Org Biomol Chem 14:10208–10216CrossRefGoogle Scholar
  157. 157.
    Lim D, Byun WG, Koo JY, Park H, Park SB (2016) Discovery of a small-molecule inhibitor of protein-microRNA interaction using binding assay with a site-specifically labeled Lin28. J Am Chem Soc 138:13630–13638CrossRefGoogle Scholar
  158. 158.
    Hermann T (2017) Viral RNA targets and their small molecule ligands. Topics Med Chem. doi: 10.1007/7355_2016_20
  159. 159.
    Wirmer J, Westhof E (2006) Molecular contacts between antibiotics and the 30S ribosomal particle. Methods Enzymol 415:180–202CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry, College of Pharmacy, and Program in Chemical BiologyUniversity of MichiganAnn ArborUSA

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