Design, synthesis, antiviral activity, and pre-formulation development of poly-L-arginine-fatty acyl derivatives of nucleoside reverse transcriptase inhibitors

Nucleosides Nucleotides Nucleic Acids. 2015;34(1):1-15. doi: 10.1080/15257770.2014.945649.


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.

Keywords: anti-HIV agents; fatty acids; lipophilicity; nucleosides; polyarginine; reverse transcriptase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Cell-Penetrating Peptides / chemistry
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / chemistry
  • Deoxyribonucleosides / chemical synthesis*
  • Deoxyribonucleosides / chemistry
  • Deoxyribonucleosides / pharmacology
  • Dicarboxylic Acids / chemistry
  • Dideoxynucleosides / chemistry
  • Emtricitabine
  • Humans
  • Lamivudine / analogs & derivatives
  • Peptides / chemistry*
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology


  • Anti-HIV Agents
  • Cell-Penetrating Peptides
  • Deoxyribonucleosides
  • Dicarboxylic Acids
  • Dideoxynucleosides
  • Peptides
  • Reverse Transcriptase Inhibitors
  • Deoxycytidine
  • polyarginine
  • Lamivudine
  • Emtricitabine
  • alovudine