title: Toward targeting RNA structure: branched peptides as cell-permeable ligands to TAR RNA.
abstract: Rational design of RNA ligands continues to be a formidable challenge, but the potential powerful applications in biology and medicine catapults it to the forefront of chemical research. Indeed, small molecule and macromolecular intervention are attractive approaches, but selectivity and cell permeability can be a hurdle. An alternative strategy is to use molecules of intermediate molecular weight that possess large enough surface area to maximize interaction with the RNA structure but are small enough to be cell-permeable. Herein, we report the discovery of nontoxic and cell-permeable branched peptide (BP) ligands that bind to TAR RNA in the low micromolar range from on-bead high-throughput screening of 4,096 compounds. TAR is a short RNA motif in the 5'-UTR of HIV-1 that is responsible for efficient generation of full RNA transcripts. We demonstrate that BPs are selective for the native TAR RNA structure and that "branching" in peptides provides multivalent interaction, which increases binding affinity to RNA.
authors: Department of Chemistry, Virginia Tech, Blacksburg, 24061, United States.
authors: David I
authors: DI
authors: Bryson
authors: Wenyu
authors: W
authors: Zhang
authors: Patrick M
authors: PM
authors: McLendon
authors: Theresa M
authors: TM
authors: Reineke
authors: Webster L
authors: WL
authors: Santos
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D001665:Binding Sites; D002463:Cell Membrane Permeability; D005456:Fluorescent Dyes; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs / Q000235:genetics; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013194:Staining and Labeling; D013329:Structure-Activity Relationship
chemical_list: D020121:5' Untranslated Regions; D005456:Fluorescent Dyes; D008024:Ligands; D010455:Peptides; D012367:RNA, Viral