Design, Synthesis, Antiviral Activity, and Pre-formulation Development of Poly-LArginine- Fatty acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

Authors

Bhanu P. Pemmaraju, University of Rhode Island
Swapnil Malekar, University of Rhode Island
Hitesh K. Agarwal, University of Rhode IslandFollow
Rakesh Tiwari, Chapman UniversityFollow
Donghoon Oh, University of Rhode IslandFollow
Gustavo F. Doncel, Eastern Virginia Medical School
David R. Worthen, University of Rhode Island
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

2015

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.

Comments

This is an Accepted Manuscript of an article published in Nucleosides, Nucleotides and Nucleic Acids, volume 34, issue 1, in 2015. DOI: 10.1080/15257770.2014.945649

Recommended Citation

Pemmaraju, B. P., Malekar, S., Agarwal, H. K., Tiwari, R. K., Oh, D., Doncel, G. F., Worthen, D. R., Parang,, K., Design, synthesis, antiviral activity, and pre-formulation development of poly-L-arginine-fatty acyl derivatives of nucleoside reverse transcriptase inhibitors. Nucleosides, Nucleotides and Nucleic Acids (2015) 34.1, 1-15.
doi: 10.1080/15257770.2014.945649

Copyright

Taylor & Francis