title: Attenuating HIV Tat/TAR-mediated protein expression by exploring the side chain length of positively charged residues.
abstract: RNA is a drug target involved in diverse cellular functions and viral processes. Molecules that inhibit the HIV TAR RNA-Tat protein interaction may attenuate Tat/TAR-dependent protein expression and potentially serve as anti-HIV therapeutics. By incorporating positively charged residues with mixed side chain lengths, we designed peptides that bind TAR RNA with enhanced intracellular activity. Tat-derived peptides that were individually substituted with positively charged residues with varying side chain lengths were evaluated for TAR RNA binding. Positively charged residues with different side chain lengths were incorporated at each Arg and Lys position in the Tat-derived peptide to enhance TAR RNA binding. The resulting peptides showed enhanced TAR RNA binding affinity, cellular uptake, nuclear localization, proteolytic resistance, and inhibition of intracellular Tat/TAR-dependent protein expression compared to the parent Tat-derived peptide with no cytotoxicity. Apparently, the enhanced inhibition of protein expression by these peptides was not determined by RNA binding affinity, but by proteolytic resistance. Despite the high TAR binding affinity, a higher binding specificity would be necessary for practical purposes. Importantly, altering the positively charged residue side chain length should be a viable strategy to generate potentially useful RNA-targeting bioactive molecules.
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan. rpcheng@ntu.edu.tw.
authors.forename: Cheng-Hsun
authors.initials: CH
authors.lastname: Wu
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Chen
authors.forename: Shing-Lung
authors.initials: SL
authors.lastname: Liu
authors.forename: Fan-Ching
authors.initials: FC
authors.lastname: Chien
authors.forename: Chung-Yuan
authors.initials: CY
authors.lastname: Mou
authors.forename: Richard P
authors.initials: RP
authors.lastname: Cheng
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015696:Gene Products, tat / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D015696:Gene Products, tat; D010455:Peptides; D012367:RNA, Viral