Attenuating HIV Tat/TAR-mediated protein expression by exploring the side chain length of positively charged residues

Cheng Hsun Wu, Yi Ping Chen, Shing Lung Liu, Fan Ching Chien, Chung Yuan Mou, Richard P. Cheng

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11096-11104
Number of pages9
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number45
DOIs
Publication statusPublished - 2015

Fingerprint

human immunodeficiency virus
Chain length
peptides
HIV
RNA
proteins
Peptides
affinity
Proteins
tat Gene Products
activity (biology)
Molecules
molecules
drugs
Cytotoxicity

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry

Cite this

Attenuating HIV Tat/TAR-mediated protein expression by exploring the side chain length of positively charged residues. / Wu, Cheng Hsun; Chen, Yi Ping; Liu, Shing Lung; Chien, Fan Ching; Mou, Chung Yuan; Cheng, Richard P.

In: Organic and Biomolecular Chemistry, Vol. 13, No. 45, 2015, p. 11096-11104.

Research output: Contribution to journalArticle

Wu, Cheng Hsun ; Chen, Yi Ping ; Liu, Shing Lung ; Chien, Fan Ching ; Mou, Chung Yuan ; Cheng, Richard P. / Attenuating HIV Tat/TAR-mediated protein expression by exploring the side chain length of positively charged residues. In: Organic and Biomolecular Chemistry. 2015 ; Vol. 13, No. 45. pp. 11096-11104.
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