Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly-L-Arginine-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 Island
Rakesh K. Tiwari, University of Rhode Island
Donghoon Oh, University of Rhode Island
Gustavo F. Doncel
David R. Worthen, University of Rhode Island
Keykavous Parang, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

2015

Department

Biomedical and Pharmaceutical Sciences

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.

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Citation/Publisher Attribution

Bhanu P. Pemmaraju, Swapnil Malekar, Hitesh K. Agarwal, Rakesh K. Tiwari, Donghoon Oh, Gustavo F. Doncel, David R. Worthen & Keykavous Parang (2015) 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, 34:1, 1-15. DOI: 10.1080/15257770.2014.945649 Available at: http://dx.doi.org/10.1080/15257770.2014.945649