title: Development of a functional backbone cyclic mimetic of the HIV-1 Tat arginine-rich motif.
abstract: We have used the backbone cyclic proteinomimetics approach to develop peptides that functionally mimic the arginine-rich motif (ARM) of the HIV-1 Tat protein. This consensus sequence serves both as a nuclear localization signal (NLS) and as an RNA binding domain. Based on the NMR structure of Tat, we have designed and synthesized a backbone cyclic ARM mimetic peptide library. The peptides were screened for their ability to mediate nuclear import of the corresponding BSA conjugates in permeabilized cells. One peptide, designated "Tat11," displayed active NLS properties. Nuclear import of Tat11-BSA was found to proceed by the same distinct pathway used by the Tat-NLS and not by the common importin alpha pathway, which is used by the SV40-NLS. Most of the Tat-derived backbone cyclic peptides display selective inhibitory activity as demonstrated by the inhibition of the nuclear import mediated by the Tat-NLS and not by the SV40-NLS. The Tat-ARM-derived peptides, including Tat-11, also inhibited binding of the HIV-1 Rev-ARM to its corresponding RNA element (Rev response element) with inhibition constants of 5 nm. Here we have shown for the first time (a) a functional mimetic of a protein sequence, which activates a nuclear import receptor and (b) a mimetic of a protein sequence with a dual functionality. Tat11 is a lead compound which can potentially inhibit the HIV-1 life cycle by a dual mechanism: inhibition of nuclear import and of RNA binding.
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, and the Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Friedler
authors.forename: D
authors.initials: D
authors.lastname: Friedler
authors.forename: N W
authors.initials: NW
authors.lastname: Luedtke
authors.forename: Y
authors.initials: Y
authors.lastname: Tor
authors.forename: A
authors.initials: A
authors.lastname: Loyter
authors.forename: C
authors.initials: C
authors.lastname: Gilon
mesh_terms: D020816:Amino Acid Motifs; D019380:Anti-HIV Agents / Q000378:metabolism*; D001120:Arginine; D001665:Binding Sites; D001692:Biological Transport; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D015696:Gene Products, tat; D015497:HIV-1; D008958:Models, Molecular; D018716:Molecular Mimicry; D019913:Nuclear Localization Signals; D010456:Peptides, Cyclic; D016601:RNA-Binding Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D019380:Anti-HIV Agents; D015696:Gene Products, tat; D019913:Nuclear Localization Signals; D010456:Peptides, Cyclic; D016601:RNA-Binding Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D001120:Arginine