Attenuating HIV Tat/TAR-mediated protein expression by exploring the side chain length of positively charged residues
Journal
Organic and Biomolecular Chemistry
Journal Volume
13
Journal Issue
45
Pages
11096-11104
Date Issued
2015
Author(s)
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. ? 2015 The Royal Society of Chemistry.
SDGs
Other Subjects
Binding energy; Bins; Chain length; Chains; Enzyme activity; Molecules; Peptides; Proteins; Tar; Binding affinities; Binding specificities; Bioactive molecules; Nuclear localization; Positively charged; Protein expressions; Proteolytic resistance; Side chain lengths; RNA; anti human immunodeficiency virus agent; peptide; transactivator protein; virus RNA; amino acid sequence; cell line; chemistry; drug effects; gene expression regulation; genetics; HIV Infections; human; Human immunodeficiency virus; long terminal repeat; metabolism; Amino Acid Sequence; Anti-HIV Agents; Cell Line; Gene Expression Regulation, Viral; Gene Products, tat; HIV; HIV Infections; HIV Long Terminal Repeat; Humans; Peptides; RNA, Viral
Type
journal article