Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

Bhanu P. Pemmaraju, Swapnil Malekar, Hitesh K. Agarwal, Rakesh K. Tiwari, Donghoon Oh, Gustavo F. Doncel, David R. Worthen, Keykavous Parang

Research output: Contribution to journalArticlepeer-review

Abstract

The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalNucleosides, Nucleotides and Nucleic Acids
Volume34
Issue number1
DOIs
StatePublished - Jan 2 2015
Externally publishedYes

Keywords

  • anti-HIV agents
  • fatty acids
  • lipophilicity
  • nucleosides
  • polyarginine
  • reverse transcriptase

ASJC Scopus subject areas

  • Genetics
  • Biochemistry
  • Molecular Medicine

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