title: A Cyclic Mimic of HIV Tat Differentiates Similar TAR RNAs on the Basis of Distinct Dynamic Behaviors.
abstract: Efforts toward the development of RNA-based drug leads have been challenging because of the complexity and dynamic nature of RNA structures as therapeutic targets. The transactivation response (TAR) RNA and cognate Tat protein of HIV have long been recognized as promising antiviral targets, and recent works have identified potentially potent inhibitors of the viral RNA-protein interaction. A new class of such inhibitors, conformationally constrained cyclic peptide mimetics of Tat, has been demonstrated to inhibit the HIV life cycle. We have previously probed the complexity and dynamics of TAR RNAs in their free states, as well as conformational shifting by various peptide and small molecule ligands. In this work, we have used an ultrafast dynamics approach to probe the interactions between TAR RNAs and one of the representatives of cyclic peptide inhibitors, L22. Our studies demonstrated that cyclic L22 specifically recognizes TAR RNAs with a unique single binding site compared to two binding sites for linear Tat protein. Although both Tat and L22 bind to the TAR RNAs as a β-hairpin structure, cyclization in L22 allows it to be a more efficient ligand from a population shifting perspective. This study provided unique insights into drug design with desired properties to differentiate similar structures based on distinct dynamic behaviors.
authors.affiliation: †Department of Molecular and Cell Biology, The University of Texas at Dallas, Richardson, Texas 75080, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.affiliation: ‡Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Larry
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: †Department of Molecular and Cell Biology, The University of Texas at Dallas, Richardson, Texas 75080, United States.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: †Department of Molecular and Cell Biology, The University of Texas at Dallas, Richardson, Texas 75080, United States.
authors.forename: Tianbing
authors.initials: T
authors.lastname: Xia
authors.affiliation: ‡Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D015497:HIV-1 / Q000378:metabolism; D015498:HIV-2 / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D059370:RNA Folding / Q000187:drug effects; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D008024:Ligands; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus