Abstract
Targeting RNA using synthetic small molecules is a major challenge of current medicinal chemistry. RNA targets are indeed very promising for future drug developments since they represent essential tools in a number of biological processes, and a number of new small-molecule binders have been reported in the literature with some excellent examples already approved by the FDA. Despite the great advances made in the development of new methodologies for the identification of specific RNA ligands, some difficulties still remain to be faced since the rational design of specific ligands still remain hard to attain. In this chapter, the milestones of the field of targeting RNA using small molecules will be described together with the methodologies employed for their discovery. The different kinds of RNA targets that have been exploited so far will also be described with examples of the scaffolds that led to the best results in terms of biological activity. The current trends of the field, including the recently approved drugs against spinal muscular atrophy or the original RIBOTAC approach, will be detailed to open the perspective toward the discovery of new drugs bearing an original and extremely promising mechanism of action.
This is a preview of subscription content, log in via an institution to check access.
References
Abulwerdi FA, Xu W, Ageeli AA, Yonkunas MJ, Arun G, Nam H et al (2019) Selective small-molecule targeting of a triple helix encoded by the long noncoding RNA, MALAT1. ACS Chem Biol 14(2):223–235. https://doi.org/10.1021/acschembio.8b00807
Ambros V (2008) The evolution of our thinking about microRNAs. Nat Med 14(10):1036–1040. https://doi.org/10.1038/nm1008-1036
Angelbello AJ, Chen JL, Childs-Disney JL, Zhang P, Wang ZF, Disney MD (2018) Using genome sequence to enable the design of medicines and chemical probes. Chem Rev 118(4):1599–1663. https://doi.org/10.1021/acs.chemrev.7b00504
Bell NM, L’Hernault A, Murat P, Richards JE, Lever AM, Balasubramanian S (2013) Targeting RNA-protein interactions within the human immunodeficiency virus type 1 lifecycle. Biochemistry 52(51):9269–9274. https://doi.org/10.1021/bi401270d
Benhamou RI, Suresh BM, Tong Y, Cochrane WG, Cavett V, Vezina-Dawod S et al (2022) DNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor. Proc Natl Acad Sci U S A 119(6). https://doi.org/10.1073/pnas.2114971119
Blond A, Ennifar E, Tisne C, Micouin L (2014) The design of RNA binders: targeting the HIV replication cycle as a case study. ChemMedChem 9(9):1982–1996. https://doi.org/10.1002/cmdc.201402259
Bottini A, De SK, Wu B, Tang C, Varani G, Pellecchia M (2015) Targeting Influenza A virus RNA promoter. Chem Biol Drug Des 86(4):663–673. https://doi.org/10.1111/cbdd.12534
Cao Y, Liu X, De Clercq E (2009) Cessation of HIV-1 transcription by inhibiting regulatory protein Rev-mediated RNA transport. Curr HIV Res 7(1):101–108. https://doi.org/10.2174/157016209787048564
Carnevali M, Parsons J, Wyles DL, Hermann T (2010) A modular approach to synthetic RNA binders of the hepatitis C virus internal ribosome entry site. Chembiochem 11(10):1364–1367. https://doi.org/10.1002/cbic.201000177
Chapman RL, Stanley TB, Hazen R, Garvey EP (2002) Small molecule modulators of HIV Rev/Rev response element interaction identified by random screening. Antivir Res 54(3):149–162. https://doi.org/10.1016/s0166-3542(01)00222-4
Cheung AK, Hurley B, Kerrigan R, Shu L, Chin DN, Shen Y et al (2018) Discovery of small molecule splicing modulators of survival motor neuron-2 (SMN2) for the treatment of spinal muscular atrophy (SMA). J Med Chem 61(24):11021–11036. https://doi.org/10.1021/acs.jmedchem.8b01291
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(11):745–754. https://doi.org/10.1021/cb700174r
Childs-Disney JL, Hoskins J, Rzuczek SG, Thornton CA, Disney MD (2012a) Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive. ACS Chem Biol 7(5):856–862. https://doi.org/10.1021/cb200408a
Childs-Disney JL, Parkesh R, Nakamori M, Thornton CA, Disney MD (2012b) Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1. ACS Chem Biol 7(12):1984–1993. https://doi.org/10.1021/cb3001606
Childs-Disney JL, Yildirim I, Park H, Lohman JR, Guan L, Tran T et al (2014) Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. ACS Chem Biol 9(2):538–550. https://doi.org/10.1021/cb4007387
Childs-Disney JL, Yang X, Gibaut QMR, Tong Y, Batey RT, Disney MD (2022) Targeting RNA structures with small molecules. Nat Rev Drug Discov. https://doi.org/10.1038/s41573-022-00521-4
Costales MG, Haga CL, Velagapudi SP, Childs-Disney JL, Phinney DG, Disney MD (2017) Small molecule inhibition of microRNA-210 reprograms an oncogenic hypoxic circuit. J Am Chem Soc 139(9):3446–3455. https://doi.org/10.1021/jacs.6b11273
Costales MG, Matsumoto Y, Velagapudi SP, Disney MD (2018) Small molecule targeted recruitment of a nuclease to RNA. J Am Chem Soc 140(22):6741–6744. https://doi.org/10.1021/jacs.8b01233
Costales MG, Suresh B, Vishnu K, Disney MD (2019) Targeted degradation of a hypoxia-associated non-coding RNA enhances the selectivity of a small molecule interacting with RNA. Cell Chem Biol 26(8):1180–1186 e5. https://doi.org/10.1016/j.chembiol.2019.04.008
Crooke ST, Baker BF, Crooke RM, Liang XH (2021) Antisense technology: an overview and prospectus. Nat Rev Drug Discov 20(6):427–453. https://doi.org/10.1038/s41573-021-00162-z
Di Giorgio A, Tran TP, Duca M (2016) Small-molecule approaches toward the targeting of oncogenic miRNAs: roadmap for the discovery of RNA modulators. Future Med Chem 8(7):803–816. https://doi.org/10.4155/fmc-2016-0018
Dibrov SM, Ding K, Brunn ND, Parker MA, Bergdahl BM, Wyles DL et al (2012) Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches. Proc Natl Acad Sci U S A 109(14):5223–5228. https://doi.org/10.1073/pnas.1118699109
Dibrov SM, Parsons J, Carnevali M, Zhou S, Rynearson KD, Ding K et al (2014) Hepatitis C virus translation inhibitors targeting the internal ribosomal entry site. J Med Chem 57(5):1694–1707. https://doi.org/10.1021/jm401312n
Disney MD, Angelbello AJ (2016) Rational design of small molecules targeting Oncogenic noncoding RNAs from sequence. Acc Chem Res 49(12):2698–2704. https://doi.org/10.1021/acs.accounts.6b00326
Disney MD, Liu B, Yang WY, Sellier C, Tran T, Charlet-Berguerand N et al (2012) A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome. ACS Chem Biol 7(10):1711–1718. https://doi.org/10.1021/cb300135h
Donlic A, Hargrove AE (2018) Targeting RNA in mammalian systems with small molecules. Wiley Interdiscip Rev RNA 9(4):e1477. https://doi.org/10.1002/wrna.1477
Donlic A, Morgan BS, Xu JL, Liu A, Roble Jr C, Hargrove AE (2018) Discovery of small molecule ligands for MALAT1 by tuning an RNA-binding scaffold. Angew Chem Int Ed Engl 57(40):13242–13247. https://doi.org/10.1002/anie.201808823
Donlic A, Zafferani M, Padroni G, Puri M, Hargrove AE (2020) Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans. Nucleic Acids Res 48(14):7653–7664. https://doi.org/10.1093/nar/gkaa585
Ennifar E, Paillart JC, Bodlenner A, Walter P, Weibel JM, Aubertin AM et al (2006) Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell. Nucleic Acids Res 34(8):2328–2339. https://doi.org/10.1093/nar/gkl317
Falese JP, Donlic A, Hargrove AE (2021) Targeting RNA with small molecules: from fundamental principles towards the clinic. Chem Soc Rev 50(4):2224–2243. https://doi.org/10.1039/d0cs01261k
Ganser LR, Kelly ML, Herschlag D, Al-Hashimi HM (2019) The roles of structural dynamics in the cellular functions of RNAs. Nat Rev Mol Cell Biol 20(8):474–489. https://doi.org/10.1038/s41580-019-0136-0
Guan L, Disney MD (2013) Covalent small-molecule-RNA complex formation enables cellular profiling of small-molecule-RNA interactions. Angew Chem Int Ed Engl 52(38):10010–10013. https://doi.org/10.1002/anie.201301639
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 Engl 47(39):7482–7484. https://doi.org/10.1002/anie.200801555
Gutschner T, Hammerle M, Diederichs S (2013) MALAT1 – a paradigm for long noncoding RNA function in cancer. J Mol Med (Berl) 91(7):791–801. https://doi.org/10.1007/s00109-013-1028-y
Haniff HS, Tong Y, Liu X, Chen JL, Suresh BM, Andrews RJ et al (2020) Targeting the SARS-CoV-2 RNA genome with small molecule binders and ribonuclease targeting chimera (RIBOTAC) degraders. ACS Cent Sci 6(10):1713–1721. https://doi.org/10.1021/acscentsci.0c00984
Haniff HS, Liu X, Tong Y, Meyer SM, Knerr L, Lemurell M et al (2022) A structure-specific small molecule inhibits a miRNA-200 family member precursor and reverses a type 2 diabetes phenotype. Cell Chem Biol 29(2):300–311 e10. https://doi.org/10.1016/j.chembiol.2021.07.006
Hermann T (2016) Small molecules targeting viral RNA. Wiley Interdiscip Rev RNA 7(6):726–743. https://doi.org/10.1002/wrna.1373
Howe JA, Wang H, Fischmann TO, Balibar CJ, Xiao L, Galgoci AM et al (2015) Selective small-molecule inhibition of an RNA structural element. Nature 526(7575):672–677. https://doi.org/10.1038/nature15542
Howe JA, Xiao L, Fischmann TO, Wang H, Tang H, Villafania A et al (2016) Atomic resolution mechanistic studies of ribocil: a highly selective unnatural ligand mimic of the E. coli FMN riboswitch. RNA Biol 13(10):946–954. https://doi.org/10.1080/15476286.2016.1216304
Jahromi AH, Nguyen L, Fu Y, Miller KA, Baranger AM, Zimmerman SC (2013) A novel CUG(exp).MBNL1 inhibitor with therapeutic potential for myotonic dystrophy type 1. ACS Chem Biol 8(5):1037–1043. https://doi.org/10.1021/cb400046u
Jefferson EA, Seth PP, Robinson DE, Winter DK, Miyaji A, Osgood SA et al (2004) Biaryl guanidine inhibitors of in vitro HCV-IRES activity. Bioorg Med Chem Lett 14(20):5139–5143. https://doi.org/10.1016/j.bmcl.2004.07.066
Joly JP, Mata G, Eldin P, Briant L, Fontaine-Vive F, Duca M et al (2014) Artificial nucleobase-amino acid conjugates: a new class of TAR RNA binding agents. Chemistry 20(7):2071–2079. https://doi.org/10.1002/chem.201303664
Kanoh S, Rubin BK (2010) Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev 23(3):590–615. https://doi.org/10.1128/CMR.00078-09
Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10(2):126–139. https://doi.org/10.1038/nrm2632
Kumar S, Kellish P, Robinson Jr WE, Wang D, Appella DH, Arya DP (2012) Click dimers to target HIV TAR RNA conformation. Biochemistry 51(11):2331–2347. https://doi.org/10.1021/bi201657k
Lee MM, Childs-Disney JL, Pushechnikov A, French JM, Sobczak K, Thornton CA et al (2009) Controlling the specificity of modularly assembled small molecules for RNA via ligand module spacing: targeting the RNAs that cause myotonic muscular dystrophy. J Am Chem Soc 131(47):17464–17472. https://doi.org/10.1021/ja906877y
Lee MK, Bottini A, Kim M, Bardaro Jr MF, Zhang Z, Pellecchia M et al (2014) A novel small-molecule binds to the influenza A virus RNA promoter and inhibits viral replication. Chem Commun (Camb) 50(3):368–370. https://doi.org/10.1039/c3cc46973e
Martin C, De Piccoli S, Gaysinski M, Becquart C, Azoulay S, Di Giorgio A et al (2020) Unveiling RNA-binding properties of verapamil and preparation of new derivatives as inhibitors of HIV-1 tat-TAR interaction. ChemPlusChem 85(1):207–216
Maucort C, Vo DD, Aouad S, Charrat C, Azoulay S, Di Giorgio A et al (2021) Design and implementation of synthetic RNA binders for the inhibition of miR-21 biogenesis. ACS Med Chem Lett 12(6):899–906. https://doi.org/10.1021/acsmedchemlett.0c00682
Meyer SM, Williams CC, Akahori Y, Tanaka T, Aikawa H, Tong Y et al (2020) Small molecule recognition of disease-relevant RNA structures. Chem Soc Rev 49(19):7167–7199. https://doi.org/10.1039/d0cs00560f
Morgan BS, Sanaba BG, Donlic A, Karloff DB, Forte JE, Zhang Y et al (2019) R-BIND: an interactive database for exploring and developing RNA-targeted chemical probes. ACS Chem Biol 14(12):2691–2700. https://doi.org/10.1021/acschembio.9b00631
Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z et al (2014) Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345(6197):688–693. https://doi.org/10.1126/science.1250127
Nguyen F, Starosta AL, Arenz S, Sohmen D, Donhofer A, Wilson DN (2014) Tetracycline antibiotics and resistance mechanisms. Biol Chem 395(5):559–575. https://doi.org/10.1515/hsz-2013-0292
Park SJ, Kim YG, Park HJ (2011) Identification of RNA pseudoknot-binding ligand that inhibits the −1 ribosomal frameshifting of SARS-coronavirus by structure-based virtual screening. J Am Chem Soc 133(26):10094–10100. https://doi.org/10.1021/ja1098325
Parkesh R, Childs-Disney JL, Nakamori M, Kumar A, Wang E, Wang T et al (2012) Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching. J Am Chem Soc 134(10):4731–4742. https://doi.org/10.1021/ja210088v
Parsons J, Castaldi MP, Dutta S, Dibrov SM, Wyles DL, Hermann T (2009) Conformational inhibition of the hepatitis C virus internal ribosome entry site RNA. Nat Chem Biol 5(11):823–825. https://doi.org/10.1038/nchembio.217
Paul R, Dutta D, Paul R, Dash J (2020) Target-directed azide-alkyne cycloaddition for assembling HIV-1 TAR RNA binding ligands. Angew Chem Int Ed Engl 59(30):12407–12411. https://doi.org/10.1002/anie.202003461
Prado S, Beltran M, Moreno A, Bedoya LM, Alcami J, Gallego J (2018) A small-molecule inhibitor of HIV-1 Rev function detected by a diversity screen based on RRE-Rev interference. Biochem Pharmacol 156:68–77. https://doi.org/10.1016/j.bcp.2018.07.040
Ratni H, Scalco RS, Stephan AH (2021) Risdiplam, the first approved small molecule splicing modifier drug as a blueprint for future transformative medicines. ACS Med Chem Lett 12(6):874–877. https://doi.org/10.1021/acsmedchemlett.0c00659
Rzuczek SG, Park H, Disney MD (2014) A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Angew Chem Int Ed Engl 53(41):10956–10959. https://doi.org/10.1002/anie.201406465
Rzuczek SG, Colgan LA, Nakai Y, Cameron MD, Furling D, Yasuda R et al (2017) Precise small-molecule recognition of a toxic CUG RNA repeat expansion. Nat Chem Biol 13(2):188–193. https://doi.org/10.1038/nchembio.2251
Seth PP, Miyaji A, Jefferson EA, Sannes-Lowery KA, Osgood SA, Propp SS et al (2005) SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain. J Med Chem 48(23):7099–7102. https://doi.org/10.1021/jm050815o
Shi Z, Zhang J, Qian X, Han L, Zhang K, Chen L et al (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(17):5519–5531. https://doi.org/10.1158/0008-5472.CAN-13-0280
Spizek J, Rezanka T (2017) Lincosamides: chemical structure, biosynthesis, mechanism of action, resistance, and applications. Biochem Pharmacol 133:20–28. https://doi.org/10.1016/j.bcp.2016.12.001
Staedel C, Tran TPA, Giraud J, Darfeuille F, Di Giorgio A, Tourasse NJ et al (2018) Modulation of oncogenic miRNA biogenesis using functionalized polyamines. Sci Rep 8(1):1667. https://doi.org/10.1038/s41598-018-20053-5
Stelzer AC, Frank AT, Kratz JD, Swanson MD, Gonzalez-Hernandez MJ, Lee J et al (2011) Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble. Nat Chem Biol 7(8):553–559. https://doi.org/10.1038/nchembio.596
Sztuba-Solinska J, Shenoy SR, Gareiss P, Krumpe LR, Le Grice SF, O’Keefe BR et al (2014) Identification of biologically active, HIV TAR RNA-binding small molecules using small molecule microarrays. J Am Chem Soc 136(23):8402–8410. https://doi.org/10.1021/ja502754f
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 Engl 49(22):3816–3818. https://doi.org/10.1002/anie.200907257
Velagapudi SP, Gallo SM, Disney MD (2014) Sequence-based design of bioactive small molecules that target precursor microRNAs. Nat Chem Biol 10(4):291–297. https://doi.org/10.1038/nchembio.1452
Velagapudi SP, Cameron MD, Haga CL, Rosenberg LH, Lafitte M, Duckett DR et al (2016) Design of a small molecule against an oncogenic noncoding RNA. Proc Natl Acad Sci U S A 113(21):5898–5903. https://doi.org/10.1073/pnas.1523975113
Vicens Q, Mondragon E, Reyes FE, Coish P, Aristoff P, Berman J et al (2018) Structure-activity relationship of Flavin analogues that target the Flavin mononucleotide riboswitch. ACS Chem Biol 13(10):2908–2919. https://doi.org/10.1021/acschembio.8b00533
Vo DD, Tran TP, Staedel C, Benhida R, Darfeuille F, Di Giorgio A et al (2016) Oncogenic MicroRNAs biogenesis as a drug target: structure-activity relationship studies on new aminoglycoside conjugates. Chemistry 22(15):5350–5362. https://doi.org/10.1002/chem.201505094
Vo DD, Becquart C, Tran TPA, Di Giorgio A, Darfeuille F, Staedel C et al (2018) Building of neomycin-nucleobase-amino acid conjugates for the inhibition of oncogenic miRNAs biogenesis. Org Biomol Chem 16(34):6262–6274. https://doi.org/10.1039/c8ob01858h
Waheed AA, Freed EO (2012) HIV type 1 gag as a target for antiviral therapy. AIDS Res Hum Retrovir 28(1):54–75. https://doi.org/10.1089/AID.2011.0230
Wang W, Preville P, Morin N, Mounir S, Cai W, Siddiqui MA (2000) Hepatitis C viral IRES inhibition by phenazine and phenazine-like molecules. Bioorg Med Chem Lett 10(11):1151–1154. https://doi.org/10.1016/s0960-894x(00)00217-1
Warner KD, Hajdin CE, Weeks KM (2018) Principles for targeting RNA with drug-like small molecules. Nat Rev Drug Discov 17(8):547–558. https://doi.org/10.1038/nrd.2018.93
Wilson DN (2014) Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol 12(1):35–48. https://doi.org/10.1038/nrmicro3155
Wilson DN, Schluenzen F, Harms JM, Starosta AL, Connell SR, Fucini P (2008) The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc Natl Acad Sci U S A 105(36):13339–13344. https://doi.org/10.1073/pnas.0804276105
Wong CH, Nguyen L, Peh J, Luu LM, Sanchez JS, Richardson SL et al (2014) Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor. J Am Chem Soc 136(17):6355–6361. https://doi.org/10.1021/ja5012146
Yamagami R, Sieg JP, Bevilacqua PC (2021) Functional roles of chelated magnesium ions in RNA folding and function. Biochemistry 60(31):2374–2386. https://doi.org/10.1021/acs.biochem.1c00012
Yang WY, Gao R, Southern M, Sarkar PS, Disney MD (2016a) Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10. Nat Commun 7:11647. https://doi.org/10.1038/ncomms11647
Yang WY, He F, Strack RL, Oh SY, Frazer M, Jaffrey SR et al (2016b) Small molecule recognition and tools to study modulation of r(CGG)(exp) in fragile X-associated tremor ataxia syndrome. ACS Chem Biol 11(9):2456–2465. https://doi.org/10.1021/acschembio.6b00147
Ye F, Haniff HS, Suresh BM, Yang D, Zhang P, Crynen G et al (2022) Rational approach to identify RNA targets of natural products enables identification of nocathiacin as an inhibitor of an oncogenic RNA. ACS Chem Biol 17(2):474–482. https://doi.org/10.1021/acschembio.1c00952
Zafferani M, Hargrove AE (2021) Small molecule targeting of biologically relevant RNA tertiary and quaternary structures. Cell Chem Biol 28(5):594–609. https://doi.org/10.1016/j.chembiol.2021.03.003
Zhang L, Abendroth F, Vazquez O (2022) A chemical biology perspective to therapeutic regulation of RNA splicing in spinal muscular atrophy (SMA). ACS Chem Biol 17(6):1293–1307. https://doi.org/10.1021/acschembio.2c00161
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Section Editor information
Rights and permissions
Copyright information
© 2023 Springer Nature Singapore Pte Ltd.
About this entry
Cite this entry
Bonnet, M., Duca, M. (2023). Chemical Tools to Target Noncoding RNAs. In: Sugimoto, N. (eds) Handbook of Chemical Biology of Nucleic Acids. Springer, Singapore. https://doi.org/10.1007/978-981-16-1313-5_36-1
Download citation
DOI: https://doi.org/10.1007/978-981-16-1313-5_36-1
Received:
Accepted:
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-16-1313-5
Online ISBN: 978-981-16-1313-5
eBook Packages: Springer Reference Chemistry and Mat. ScienceReference Module Physical and Materials ScienceReference Module Chemistry, Materials and Physics