{"doi":"10.1101/2020.05.02.074336","title":"Revealing the high propensity of RNAs to non-specifically bind drug-like small molecules","abstract":"ABSTRACT Identifying small molecules that selectively bind a single RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to non-specific binding of aminoglycosides and intercalators to a variety of RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities, however the ability of such compounds to discriminate against RNA stem-loops commonly found in the transcriptome has not been thoroughly assessed in all cases. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activity of three distinct RNAs, to non-specifically bind two HIV-1 stem-loop RNAs: the transactivation response element (TAR) and stem IIB in the rev response element (RREIIB). All three compounds bound to TAR and RREIIB in vitro , and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting substantial off-target interactions consistent with non-specific cellular activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem-loop RNA motifs, much like aminoglycosides, and in contrast to ligands that specifically bind riboswitches. Our results support extending the group of non-selective RNA-binders beyond aminoglycosides and intercalators to encompass drug-like compounds with capacity for non-specific hydrogen-bonding and reinforce the importance of assaying for off-target interactions and RNA selectivity in vitro and in cells when assessing novel RNA-binders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129461,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":467478,"name":"Chia-Chieh Chu","orcid":"0000-0003-4480-4337","position":1,"is_corresponding":false},{"id":259596,"name":"Honglue Shi","orcid":"0000-0003-3847-1652","position":2,"is_corresponding":false},{"id":467477,"name":"Laura R. Ganser","orcid":"0000-0002-7357-4588","position":3,"is_corresponding":false},{"id":467479,"name":"Hal P. Bogerd","orcid":"0000-0002-1682-013X","position":4,"is_corresponding":false},{"id":478033,"name":"Kelly Huynh","orcid":null,"position":5,"is_corresponding":false},{"id":476951,"name":"Yuze Hou","orcid":"0000-0001-5111-265X","position":6,"is_corresponding":false},{"id":247476,"name":"Bryan R. Cullen","orcid":"0000-0002-8638-6850","position":7,"is_corresponding":false},{"id":259604,"name":"Hashim M. Al‐Hashimi","orcid":"0000-0003-0681-1747","position":8,"is_corresponding":false},{"id":468542,"name":"Megan L. Kelly","orcid":null,"position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":null,"created_at":"2026-07-18T23:15:45.920615Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}