Small-molecule-mediated RNA targeting: emerging strategies and therapeutic potential of RiboTAC

Abstract

Many disease-associated proteins are difficult to target using conventional small molecules or biologics. RNA offers a promising therapeutic strategy because its structural motifs can create recognition sites for regulatory proteins and small molecules, enabling intervention upstream of proteins that are otherwise considered "undruggable". Recent advances in RNA-targeting therapeutics, particularly RNA-binding small molecules, have demonstrated the feasibility of selectively modulating RNA maturation, splicing, translation, and degradation. However, their broader clinical application is still limited by non-specific toxicity, off-target effects, stability concerns, and delivery challenges. Targeted protein degradation is a remarkable therapeutic modality that has been widely used to target undruggable pathogenic proteins. In relation to this, a currently emerging research field is that of ribonuclease-targeting chimeras (RiboTACs). Unlike the "occupancy-based" mode of small-molecule inhibitors (SMIs), RiboTACs recruit endogenous ribonucleases to selectively degrade disease-associated RNA transcripts through an event-driven mechanism, which enables efficient removal of pathogenic RNAs while offering advantages with regard to medicinal chemistry optimization compared with oligonucleotide-based approaches. In this perspective, we systematically summarize the classification of targetable RNAs, recent advances in RNA-targeting small molecules, and the design principles, applications, and future challenges of RiboTACs.

Acknowledgments

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 82322073, 82173846, 82430119, 82304790, and 82304533), Shanghai Rising-Star Program (No. 22QA1409100), Oriental Scholars of Shanghai (TP2022081), Jiangxi Province Thousand Talents Program (jxsq2023102168), Shanghai Shuguang Program (No. 24SG40), the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine (2023YZZ02), National Key R&D Program of China (Grant No. 2024YFC3506603), Shanghai Sailing Program (No. 23YF1442600), the grant from the State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine (SHUTCM-SKL-202509, SHUTCM-SKL-202520), CAMS Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-3-009), Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (2060302), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2025-2027)-2-2-1], High level Key Discipline of National Administration of Traditional Chinese Medicine (No. zyyzdxk-2023071), and Innovation team of high-level local universities in Shanghai: Strategic Innovation Team of TCM Chemical Biology, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine (20DZ2272200). We acknowledge the online drawing software for supporting the figure creation (BioRender, https://biorender.com).

Ethical statements

Not applicable.

Author contributions

The authors confirm their contributions to the work as follows: conception and design: Jin J, Luan X; draft manuscript preparation: Zhou W, Jin J; analysis and interpretation: Wu Y, Chen H, Zhang W. All authors reviewed and approved the final version of the manuscript.

Data availability

Data sharing is not applicable to this review as no datasets were generated or analyzed.

Conflict of interest

The authors declare that they have no conflict of interest.

References

[1] Warner KD, Hajdin CE, Weeks KM. 2018. Principles for targeting RNA with drug-like small molecules. Nature Reviews Drug Discovery 17: 547-558

[2] The ENCODE Project Consortium. 2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57-74

[3] Saraswat A, Patki M, Fu Y, Barot S, Dukhande VV, et al. 2020. Nanoformulation of PROteolysis TArgeting Chimera targeting 'undruggable' c-Myc for the treatment of pancreatic cancer . Nanomedicine 15: 1761-1777

[4] ClinicalTrials.gov. 2026. Search of RNA-targeting therapeutics clinical trials. U.S. National Library of Medicine . https://clinicaltrials.gov/ (accessed on 17 May 2026)

[5] Khorkova O, Stahl J, Joji A, Volmar CH, Wahlestedt C. 2023. Amplifying gene expression with RNA-targeted therapeutics. Nature Reviews Drug Discovery 22: 539-561

[6] Childs-Disney JL, Tsitovich PB, Disney MD. 2011. Using modularly assembled ligands to bind RNA internal loops separated by different distances. ChemBioChem 12: 2143-2146

[7] Menduti G, Rasà DM, Stanga S, Boido M. 2020. Drug screening and drug repositioning as promising therapeutic approaches for spinal muscular atrophy treatment. Frontiers in Pharmacology 11: 592234

[8] Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, et al. 2018. Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA). Journal of Medicinal Chemistry 61: 6501-6517

[9] Dhillon S. 2020. Risdiplam: first approval. Drugs 80: 1853-1858

[10] Xiao L, Kang S, Djordjevic D, Gonorazky H, Chiang J, et al. 2023. Understanding caregiver experiences with disease-modifying therapies for spinal muscular atrophy: a qualitative study. Archives of Disease in Childhood 108: 929-934

[11] Childs-Disney JL, Yang X, Gibaut QMR, Tong Y, Batey RT, et al. 2022. Targeting RNA structures with small molecules. Nature Reviews Drug Discovery 21: 736-762

[12] Tong Y, Lee Y, Liu X, Childs-Disney JL, Suresh BM, et al. 2023. Programming inactive RNA-binding small molecules into bioactive degraders. Nature 618: 169-179

[13] Tong Y, Gibaut QMR, Rouse W, Childs-Disney JL, Suresh BM, et al. 2022. Transcriptome-wide mapping of small-molecule RNA-binding sites in cells informs an isoform-specific degrader of QSOX1 mRNA . Journal of the American Chemical Society 144: 11620-11625

[14] Xiong W, Liu X, Qi Q, Li Y, Huang S, et al. 2025. Bioorthogonal RNase L recruitment enables targeted inducible degradation of SARS-CoV-2 RNA. Angewandte Chemie International Edition 64: e202515064

[15] Bian T, Gao S, Sun X, Zhou S, Pei Y, et al. 2025. Single-molecule detection on intrastrand interactions among G4 clusters. Analytical Chemistry 97: 11617-11626

[16] Zhao L, Zhao J, Zhong K, Tong A, Jia D. 2022. Targeted protein degradation: mechanisms, strategies and application. Signal Transduction and Targeted Therapy 7: 113

[17] Fang Y, Wang J, Zhao M, Zheng Q, Ren C, et al. 2022. Progress and challenges in targeted protein degradation for neurodegenerative disease therapy. Journal of Medicinal Chemistry 65: 11454-11477

[18] Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, et al. 2001. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America 98: 8554-8559

[19] Domostegui A, Nieto-Barrado L, Perez-Lopez C, Mayor-Ruiz C. 2022. Chasing molecular glue degraders: screening approaches. Chemical Society Reviews 51: 5498-5517

[20] Wu S, Xiao H, Sun Q. 2021. New approaches for small molecule-induced protein degradation. Future Medicinal Chemistry 13: 439-441

[21] Henning NJ, Boike L, Spradlin JN, Ward CC, Liu G, et al. 2022. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nature Chemical Biology 18: 412-421

[22] Chen P-H, Hu Z, An E, Okeke I, Zheng S, et al. 2021. Modulation of phosphoprotein activity by phosphorylation targeting chimeras (PhosTACs). ACS Chemical Biology 16: 2808-2815

[23] Costales MG, Matsumoto Y, Velagapudi SP, Disney MD. 2018. Small molecule targeted recruitment of a nuclease to RNA. Journal of the American Chemical Society 140: 6741-6744

[24] 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 Chemical Biology 26: 1180-1186.e5

[25] Costales MG, Aikawa H, Li Y, Childs-Disney JL, Abegg D, et al. 2020. Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer. Proceedings of the National Academy of Sciences of the United States of America 117: 2406-2411

[26] Guan L, Disney MD. 2013. Small-molecule-mediated cleavage of RNA in living cells. Angewandte Chemie International Edition 52: 1462-1465

[27] Haj-Yahia S, Nandi A, Benhamou RI. 2023. Targeted degradation of structured RNAs via ribonuclease-targeting chimeras (RiboTacs). Expert Opinion on Drug Discovery 18: 929-942

[28] Kubota K, Nakahara K, Ohtsuka T, Yoshida S, Kawaguchi J, et al. 2004. Identification of 2'-phosphodiesterase, which plays a role in the 2-5A system regulated by interferon. Journal of Biological Chemistry 279: 37832-37841

[29] Kargbo RB. 2021. RIBOTACs: small molecules selectively destroy cancer-associated RNA. ACS Medicinal Chemistry Letters 12: 1872-1873

[30] Liang X-H, Sun H, Shen W, Crooke ST. 2015. Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages. Nucleic Acids Research 43: 2927-2945

[31] Wang W, He S, Dong G, Sheng C. 2022. Nucleic-acid-based targeted degradation in drug discovery. Journal of Medicinal Chemistry 65: 10217-10232

[32] Meyer SM, Williams CC, Akahori Y, Tanaka T, Aikawa H, et al. 2020. Small molecule recognition of disease-relevant RNA structures. Chemical Society Reviews 49: 7167-7199

[33] Gao X, Wu Z. 2025. IRES-mediated translation: expanding the toolkits of RNA therapy. International Journal of Molecular Sciences 26: 10542

[34] Khaskia E, Dahatonde D, Benhamou RI. 2025. RNA G-quadruplex RIBOTAC-mediated targeted degradation of lncRNA TERRA. Advanced Science 12: e12715

[35] Cullen BR. 2004. Transcription and processing of human microRNA precursors. Molecular Cell 16: 861-865

[36] Ha M, Kim VN. 2014. Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biology 15: 509-524

[37] Bohnsack MT, Czaplinski K, Gorlich D. 2004. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10: 185-191

[38] Starega-Roslan J, Galka-Marciniak P, Krzyzosiak WJ. 2015. Nucleotide sequence of miRNA precursor contributes to cleavage site selection by Dicer. Nucleic Acids Research 43: 10939-10951

[39] Childs-Disney JL, Disney MD. 2015. Small molecule targeting of a microRNA associated with hepatocellular carcinoma. ACS Chemical Biology 11: 375-380

[40] Costales MG, Haga CL, Velagapudi SP, Childs-Disney JL, Phinney DG, et al. 2017. Small molecule inhibition of microRNA-210 reprograms an oncogenic hypoxic circuit. Journal of the American Chemical Society 139: 3446-3455

[41] Gilam A, Conde J, Weissglas-Volkov D, Oliva N, Friedman E, et al. 2016. Local microRNA delivery targets Palladin and prevents metastatic breast cancer. Nature Communications 7: 12868

[42] Velagapudi SP, Gallo SM, Disney MD. 2014. Sequence-based design of bioactive small molecules that target precursor microRNAs. Nature Chemical Biology 10: 291-297

[43] Velagapudi SP, Cameron MD, Haga CL, Rosenberg LH, Lafitte M, et al. 2016. Design of a small molecule against an oncogenic noncoding RNA. Proceedings of the National Academy of Sciences of the United States of America 113: 5898-5903

[44] Li Y, Disney MD. 2018. Precise small molecule degradation of a noncoding RNA identifies cellular binding sites and modulates an oncogenic phenotype. ACS Chemical Biology 13: 3065-3071

[45] Kwok CK, Merrick CJ. 2017. G-quadruplexes: Prediction, characterization, and biological application. Trends in Biotechnology 35: 997-1013

[46] Rosenberg M, Paterson BM. 1979. Efficient cap-dependent translation of polycistronic prokaryotic mRNAs is restricted to the first gene in the operon. Nature 279: 696-701

[47] Davila-Calderon J, Patwardhan NN, Chiu LY, Sugarman A, Cai Z, et al. 2020. IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex. Nature Communications 11: 4775

[48] Péladeau C, Jasmin BJ. 2021. Targeting IRES-dependent translation as a novel approach for treating Duchenne muscular dystrophy. RNA Biology 18: 1238-1251

[49] Kozak M, Shatkin AJ. 1978. Migration of 40 S ribosomal subunits on messenger RNA in the presence of edeine. Journal of Biological Chemistry 253: 6568-6577

[50] Nanbru C, Lafon I, Audigier S, Gensac MC, Vagner S, et al. 1997. Alternative translation of the proto-oncogene c-myc by an internal ribosome entry site. Journal of Biological Chemistry 272: 32061-32066

[51] Lee ASY, Kranzusch PJ, Cate JHD. 2015. eIF3 targets cell-proliferation messenger RNAs for translational activation or repression. Nature 522: 111-114

[52] Lee AS, Kranzusch PJ, Doudna JA, Cate JHD. 2016. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature 536: 96-99

[53] Ding Y, Fei Y, Lu B. 2020. Emerging new concepts of degrader technologies. Trends in Pharmacological Sciences 41: 464-474

[54] Lee Y, Rio DC. 2015. Mechanisms and regulation of alternative pre-mRNA splicing. Annual Review of Biochemistry 84: 291-323

[55] Ule J, Blencowe BJ. 2019. Alternative splicing regulatory networks: functions, mechanisms, and evolution. Molecular Cell 76: 329-345

[56] Sazani P, Kole R. 2003. Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing. Journal of Clinical Investigation 112: 481-486

[57] Zheng S, Chen Y, Donahue CP, Wolfe MS, Varani G. 2009. Structural basis for stabilization of the tau pre-mRNA splicing regulatory element by novantrone (mitoxantrone). Chemistry & Biology 16: 557-566

[58] Messina S, Sframeli M. 2020. New treatments in spinal muscular atrophy: positive results and new challenges. Journal of Clinical Medicine 9: 2222

[59] Wang Z-F, Ursu A, Childs-Disney JL, Guertler R, Yang WY, et al. 2019. The hairpin form of r(G4C2)exp in c9ALS/FTD is repeat-associated non-ATG translated and a target for bioactive small molecules. Cell Chemical Biology 26: 179-190.e12

[60] Bush JA, Aikawa H, Fuerst R, Li Y, Ursu A, et al. 2021. Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(G4C2) repeat expansion in vitro and in vivo ALS models . Science Translational Medicine 13: eabd5991

[61] Kumar V, Hasan GM, Hassan MI. 2017. Unraveling the role of RNA mediated toxicity of C9orf72 repeats in C9-FTD/ALS . Frontiers in Neuroscience 11: 711

[62] Jahromi AH, Fu Y, Miller KA, Nguyen L, Luu LM, et al. 2013. Developing bivalent ligands to target CUG triplet repeats, the causative agent of myotonic dystrophy type 1. Journal of Medicinal Chemistry 56: 9471-9481

[63] Jog SP, Paul S, Dansithong W, Tring S, Comai L, et al. 2012. RNA splicing is responsive to MBNL1 dose. PLoS One 7: e48825

[64] Angelbello AJ, DeFeo ME, Glinkerman CM, Boger DL, Disney MD. 2020. Precise targeted cleavage of a r(CUG) repeat expansion in cells by using a small-molecule-deglycobleomycin conjugate. ACS Chemical Biology 15: 849-855

[65] La Spada AR, Taylor JP. 2010. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nature Reviews Genetics 11: 247-258

[66] Gendron TF, Belzil VV, Zhang YJ, Petrucelli L. 2014. Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathologica 127: 359-376

[67] Angelbello AJ, Disney MD. 2018. Bleomycin can cleave an oncogenic noncoding RNA. ChemBioChem 19: 43-47

[68] Benhamou RI, Abe M, Choudhary S, Meyer SM, Angelbello AJ, et al. 2020. Optimization of the linker domain in a dimeric compound that degrades an r(CUG) repeat expansion in cells. Journal of Medicinal Chemistry 63: 7827-7839

[69] Disney MD, Angelbello AJ. 2016. Rational design of small molecules targeting oncogenic noncoding RNAs from sequence. Accounts of Chemical Research 49: 2698-2704

[70] Garner AL, Lorenz DA, Sandoval J, Gallagher EE, Kerk SA, et al. 2019. Tetracyclines as inhibitors of pre-microRNA maturation: a disconnection between RNA binding and inhibition. ACS Medicinal Chemistry Letters 10: 816-821

[71] Pomplun S, Gates ZP, Zhang G, Quartararo AJ, Pentelute BL. 2020. Discovery of nucleic acid binding molecules from combinatorial biohybrid nucleobase peptide libraries. Journal of the American Chemical Society 142: 19642-19651

[72] Vo DD, Tran TPA, Staedel C, Benhida R, Darfeuille F, et al. 2016. Oncogenic MicroRNAs biogenesis as a drug target: structure-activity relationship studies on new aminoglycoside conjugates. Chemistry 22: 5350-5362

[73] Disney MD, Childs JL, Turner DH. 2004. Hoechst 33258 selectively inhibits group I intron self-splicing by affecting RNA folding. ChemBioChem 5: 1647-1652

[74] 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 . Journal of the American Chemical Society 133: 10111-10118

[75] Tran T, Disney MD. 2012. Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations. Nature Communications 3: 1125

[76] Parkesh R, Childs-Disney JL, Nakamori M, Kumar A, Wang E, 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 . Journal of the American Chemical Society 134: 4731-4742

[77] Guan L, Disney MD. 2013. Covalent small-molecule-RNA complex formation enables cellular profiling of small-molecule-RNA interactions. Angewandte Chemie International Edition 52: 10010-10013

[78] Disney MD, Liu B, Yang WY, Sellier C, Tran T, et al. 2012. A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome. ACS Chemical Biology 7: 1711-1718

[79] Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, et al. 2014. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83: 1043-1050

[80] Rzuczek SG, Southern MR, Disney MD. 2015. Studying a drug-like, RNA-focused small molecule library identifies compounds that inhibit RNA toxicity in myotonic dystrophy. ACS Chemical Biology 10: 2706-2715

[81] Costales MG, Hoch DG, Abegg D, Childs-Disney JL, Velagapudi SP, et al. 2019. A designed small molecule inhibitor of a non-coding RNA sensitizes HER2 negative cancers to Herceptin. Journal of the American Chemical Society 141: 2960-2974

[82] Suresh BM, Li W, Zhang P, Wang KW, Yildirim I, et al. 2020. A general fragment-based approach to identify and optimize bioactive ligands targeting RNA. Proceedings of the National Academy of Sciences of the United States of America 117: 33197-33203

[83] Haniff HS, Knerr L, Liu X, Crynen G, Boström J, et al. 2020. Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold-small molecule interactions. Nature Chemistry 12: 952-961

[84] Wagner-Griffin S, Abe M, Benhamou RI, Angelbello AJ, Vishnu K, et al. 2021. A druglike small molecule that targets r(CCUG) repeats in myotonic dystrophy type 2 facilitates degradation by RNA quality control pathways. Journal of Medicinal Chemistry 64: 8474-8485

[85] Angelbello AJ, Benhamou RI, Rzuczek SG, Choudhary S, Tang Z, et al. 2021. A small molecule that binds an RNA repeat expansion stimulates its decay via the exosome complex . Cell Chemical Biology 28: 34-45.e6

[86] Tong Y, Zhang P, Yang X, Liu X, Zhang J, et al. 2024. Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease-targeting chimera. Proceedings of the National Academy of Sciences of the United States of America 121: e2306682120

[87] Meyer SM, Tanaka T, Zanon PRA, Baisden JT, Abegg D, et al. 2022. DNA-encoded library screening to inform design of a ribonuclease targeting chimera (RiboTAC). Journal of the American Chemical Society 144: 21096-21102

[88] Liu X, Haniff HS, Childs-Disney JL, Shuster A, Aikawa H, et al. 2020. Targeted degradation of the oncogenic MicroRNA 17-92 cluster by structure-targeting ligands. Journal of the American Chemical Society 142: 6970-6982

[89] Disney MD, Childs‐Disney JL. 2007. Using selection to identify and chemical microarray to study the RNA internal loops recognized by 6'-N-acylated Kanamycin A. ChemBioChem 8: 649-656

[90] Disney MD, Labuda LP, Paul DJ, Poplawski SG, Pushechnikov A, et al. 2008. Two-dimensional combinatorial screening identifies specific aminoglycoside-RNA internal loop partners. Journal of the American Chemical Society 130: 11185-11194

[91] Lee MM, Pushechnikov A, Disney MD. 2009. Rational and modular design of potent ligands targeting the RNA that causes myotonic dystrophy 2. ACS Chemical Biology 4: 345-355

[92] Kumar A, Parkesh R, Sznajder LJ, Childs-Disney JL, Sobczak K, et al. 2012. Chemical correction of pre-mRNA splicing defects associated with sequestration of muscleblind-like 1 protein by expanded r(CAG)-containing transcripts. ACS Chemical Biology 7: 496-505

[93] Yang WY, Gao R, Southern M, Sarkar PS, Disney MD. 2016. Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10. Nature Communications 7: 11647

[94] Childs-Disney JL, Stepniak-Konieczna E, Tran T, Yildirim I, Park H, et al. 2013. Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules. Nature Communications 4: 2044

[95] Haga CL, Velagapudi SP, Strivelli JR, Yang W-Y, Disney MD, et al. 2015. Small molecule inhibition of miR-544 biogenesis disrupts adaptive responses to hypoxia by modulating ATM-mTOR signaling. ACS Chemical Biology 10: 2267-2276

[96] Hoskins JW, Ofori LO, Chen CZ, Kumar A, Sobczak K, et al. 2014. Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects. Nucleic Acids Research 42: 6591-6602

[97] Velagapudi SP, Costales MG, Vummidi BR, Nakai Y, Angelbello AJ, et al. 2018. Approved anti-cancer drugs target oncogenic non-coding RNAs. Cell Chemical Biology 25: 1086-1094.e7

[98] Haniff HS, Tong Y, Liu X, Chen JL, Suresh BM, et al. 2020. Targeting the SARS-CoV-2 RNA genome with small molecule binders and ribonuclease targeting chimera (RIBOTAC) degraders. ACS Central Science 6: 1713-1721

[99] Ursu A, Baisden JT, Bush JA, Taghavi A, Choudhary S, et al. 2021. A small molecule exploits hidden structural features within the RNA repeat expansion that causes c9ALS/FTD and rescues pathological hallmarks. ACS Chemical Neuroscience 12: 4076-4089

[100] Suresh BM, Akahori Y, Taghavi A, Crynen G, Gibaut QMR, et al. 2022. Low-molecular weight small molecules can potently bind RNA and affect oncogenic pathways in cells. Journal of the American Chemical Society 144: 20815-20824

[101] Pernodet N, Hermetet F, Adami P, Vejux A, Descotes F, et al. 2012. High expression of QSOX1 reduces tumorogenesis, and is associated with a better outcome for breast cancer patients. Breast Cancer Research 14: R136

[102] Suresh BM, Tong Y, Abegg D, Adibekian A, Childs-Disney JL, et al. 2023. Altering the cleaving effector in chimeric molecules that target RNA enhances cellular selectivity. ACS Chemical Biology 18: 2385-2393

[103] Wirth B. 2000. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Human Mutation 15: 228-237

[104] Palacino J, Swalley SE, Song C, Cheung AK, Shu L, et al. 2015. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nature Chemical Biology 11: 511-517

[105] Mercure S, Montplaisir S, Lemay G. 1993. Correlation between the presence of a self-splicing intron in the 25S rDNA of C.albicans and strains susceptibility to 5-fluorocytosine. Nucleic Acids Research 21: 6020-6027

[106] Bubenik JL, Scotti MM, Swanson MS. 2024. Therapeutic targeting of RNA for neurological and neuromuscular disease. Genes & Development 38: 698-717

[107] Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, et al. 2000. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407: 340-348

[108] Moazed D, Noller HF. 1987. Interaction of antibiotics with functional sites in 16S ribosomal RNA. Nature 327: 389-394

[109] Recht MI, Fourmy D, Blanchard SC, Dahlquist KD, Puglisi JD. 1996. RNA sequence determinants for aminoglycoside binding to an a-site rRNA model oligonucleotide. Journal of Molecular Biology 262: 421-436

[110] Lee MM, Childs-Disney JL, Pushechnikov A, French JM, Sobczak K, 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 . Journal of the American Chemical Society 131: 17464-17472

[111] Silva JG, Carvalho I. 2007. New insights into aminoglycoside antibiotics and derivatives. Current Medicinal Chemistry 14: 1101-1119

[112] Labuda LP, Pushechnikov A, Disney MD. 2009. Small molecule microarrays of RNA-focused peptoids help identify inhibitors of a pathogenic group I intron. ACS Chemical Biology 4: 299-307

[113] Li H, Dong J, Cai M, Xu Z, Cheng X-D, et al. 2021. Protein degradation technology: a strategic paradigm shift in drug discovery. Journal of Hematology & Oncology 14: 138

[114] Mikutis S, Rebelo M, Yankova E, Gu M, Tang C, et al. 2023. Proximity-induced nucleic acid degrader (PINAD) approach to targeted RNA degradation using small molecules. ACS Central Science 9: 892-904

[115] Bonet-Aleta J, Maehara T, Craig BA, Bernardes GJL. 2024. Small molecule RNA degraders. Angewandte Chemie International Edition 63: e202412925

[116] Ursu A, Childs-Disney JL, Andrews RJ, O’Leary CA, Meyer SM, et al. 2020. Design of small molecules targeting RNA structure from sequence. Chemical Society Reviews 49: 7252-7270

[117] Disney MD. 2019. Targeting RNA with small molecules to capture opportunities at the intersection of chemistry, biology, and medicine. Journal of the American Chemical Society 141: 6776-6790

[118] Childs-Disney JL, Tran T, Vummidi BR, Velagapudi SP, Haniff HS, et al. 2018. A massively parallel selection of small molecule-RNA motif binding partners informs design of an antiviral from sequence. Chem 4: 2384-2404

[119] Garner AL, Lorenz DA, Gallagher EE. 2019. A click chemistry assay to identify natural product ligands for pre-microRNAs. Methods in Enzymology 623: 85-99

[120] Borgelt L, Haacke N, Lampe P, Qiu X, Gasper R, et al. 2022. Small-molecule screening of ribonuclease L binders for RNA degradation. Biomed Pharmacother 154: 113589

[121] Malathi K, Paranjape JM, Ganapathi R, Silverman RH. 2004. HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2', 5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. Cancer Research 64: 9144-9151

[122] Loureiro RJ, Maiti S, Mondal K, Mukherjee S, Bujnicki JM. 2025. Modeling flexible RNA 3D structures and RNA-protein complexes. Current Opinion in Structural Biology 94: 103137

[123] Dilliard SA, Cheng Q, Siegwart DJ. 2021. On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles. Proceedings of the National Academy of Sciences of the United States of America 118: e2109256118

[124] Rzuczek SG, Gao Y, Tang ZZ, Thornton CA, Kodadek T, et al. 2013. Features of modularly assembled compounds that impart bioactivity against an RNA target. ACS Chemical Biology 8: 2312-2321

[125] Sadler AJ, Williams BRG. 2008. Interferon-inducible antiviral effectors. Nature Reviews Immunology 8: 559-568

[126] Rebouillat D, Hovanessian AG. 1999. The human 2', 5'-oligoadenylate synthetase family: Interferon-induced proteins with unique enzymatic properties. Journal of Interferon & Cytokine Research 19: 295-308

[127] Takenaka Y, Yamada A, Tomioka Y, Akiyama Y, Ivanov P. 2025. RNase L produces tRNA-derived RNAs that contribute to translation inhibition. RNA 31: 961-972

[128] Tang Z, Hegde S, Hao S, Selvaraju M, Qiu J, et al. 2025. Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5' untranslated region. Nature Communications 16: 483

[129] Thakur CS, Jha BK, Dong B, Das Gupta J, Silverman KM, et al. 2007. Small-molecule activators of RNase L with broad-spectrum antiviral activity. Proceedings of the National Academy of Sciences of the United State of America 104: 9585-9590

[130] Thakur CS, Xu Z, Wang Z, Novince Z, Silverman RH. 2005. A convenient and sensitive fluorescence resonance energy transfer assay for RNase L and 2',5' oligoadenylates. Methods in Molecular Medicine 116: 103-113

[131] Zuker M. 2003. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Research 31: 3406-3415

[132] Rzuczek SG, Colgan LA, Nakai Y, Cameron MD, Furling D, et al. 2017. Precise small-molecule recognition of a toxic CUG RNA repeat expansion. Nature Chemical Biology 13: 188-193

[133] Xu W, Biswas J, Singer RH, Rosbash M. 2022. Targeted RNA editing: Novel tools to study post-transcriptional regulation. Molecular Cell 82: 389-403

[134] Meyer SM, Kovachka S, Wang T, Cameron MD, Childs-Disney JL, et al. 2025. Linker optimization enhances the potency of ribonuclease-targeting chimeras in cancer models. Journal of Medicinal Chemistry 68: 12881-12903

[135] Jiao Z, Song C, Sha X, Chen Y, Xing Y, et al. 2025. Targeted RNA degradation via LipoSM-RiboTAC nanoparticles: a versatile platform for cancer therapy . Journal of the American Chemical Society 147: 42209-42220

[136] Fang Y, Wu Q, Wang F, Liu Y, Zhang H, et al. 2025. Aptamer-RIBOTAC strategy enabling tumor-dpecific targeted degradation of microRNA for precise cancer therapy. Small Methods 9: e2400349

[137] Ellenbroek BD, Kahler JP, Evers SR, Pomplun SJ. 2024. Synthetic peptides: promising modalities for the targeting of disease-related nucleic acids. Angewandte Chemie, International Edition 63: e202401704

[138] Morishita EC, Nakamura S. 2024. Recent applications of artificial intelligence in RNA-targeted small molecule drug discovery. Expert Opinion on Drug Discovery 19: 415-431

[139] Mullowney MW, Duncan KR, Elsayed SS, Garg N, van der Hooft JJJ, et al. 2023. Artificial intelligence for natural product drug discovery. Nature Reviews Drug Discovery 22: 895-916

[140] Sato K, Hamada M. 2023. Recent trends in RNA informatics: a review of machine learning and deep learning for RNA secondary structure prediction and RNA drug discovery. Briefings in Bioinformatics 24: bbad186

[141] Disney MD, Winkelsas AM, Velagapudi SP, Southern M, Fallahi M. 2016. Inforna 2.0: a platform for the sequence-based design of small molecules targeting structured RNAs. ACS Chemical Biology 11: 1720-1728

[142] de Lajarte AA, Taillades Y, Aruda J, Bongrand P, Wightman FF, et al. 2026. Diverse database and machine learning model to narrow the generalization gap in RNA structure prediction. Science Advances 12: eadz4967

[143] Wang Y, Tang S-C. 2022. The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options. Cancer and Metastasis Reviews 41: 975-990

[144] Ravegnini E, Trabocchi A, Lenci E. 2025. Small-molecule RNA ligands: a patent review (2018-2024). Expert Opinion on Therapeutic Patents 35: 675-693

[145] Su X, Tong Y, Zanon PRA, Wang J, Tanaka T, et al. 2024. Unbiased RNA degrader identification uncovers an LC3B-recruiting chimera for COL15A1 mRNA degradation . Journal of the American Chemical Society 147: 45157-45167

[146] Su Y, Hammond MC. 2020. RNA-based fluorescent biosensors for live cell imaging of small molecules and RNAs. Current Opinion in Biotechnology 63: 157-166

[147] Seok H, Lee H, Jang E-S, Chi SW. 2018. Evaluation and control of miRNA-like off-target repression for RNA interference. Cellular and Molecular Life Sciences 75: 797-814

[148] Lee YT. 2024. Nexus between RNA conformational dynamics and functional versatility. Current Opinion in Structural Biology 89: 102942

[149] Khaskia E, Benhamou RI. 2025. Leveraging RIBOTAC technology: fluorescent RNase L probes for live-cell imaging and function analysis. Heliyon 11: e41295