Synthesis and Evaluation of a Novel Synthetic Phosphocholine Lipid‐AZT Conjugate That Double‐Targets Wild‐Type and Drug Resistant Variants of HIV

Abstract

INK‐20, a synthetic phosphocholine lipid‐AZT conjugate, was evaluated for antiviral activity against wild‐type HIV‐1, a matched pair of pre‐AZT and post‐AZT and multi‐drug resistant clinical isolates. In addition, it was tested for activity against viruses resistant to nucleoside (AZT, 3TC) and nonnucleoside (nevirapine) reverse transcriptase and protease (saquinavir) inhibitors using the syncytial plaque reduction assay for infectious virus multiplication. The EC₅₀ values were 0.004, and 0.005 µM against wild‐type HIV‐1 for INK‐20 and AZT, respectively. INK‐20 showed little or no cytotoxicity when assayed in CEM‐SS cells and four other cell types including PBMC. This resulted in a selective index of > 25,000 and > 20,000 for INK‐20 and AZT, respectively. When tested against a matched pair of pre‐AZT and post‐AZT clinical isolates, the EC₅₀ values were 0.01 and 0.03 µM for INK‐20 and 0.0005 and 0.33 µM for AZT, respectively. INK‐20 had moderate to good activity against two other AZT resistant variants and very good activity against a multi‐drug resistant clinical isolate compared to marked resistance of these viruses to AZT alone. INK‐20 retained significant activity against viruses resistant to 3TC, nevirapine, and saquinavir. The synthetic phosphocholine lipid‐AZT conjugate INK‐20 represents a novel class of anti‐HIV compounds, which may provide new strategies for the treatment of HIV drug‐resistant variants.

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

Keywords:

• Phosphocholine lipid analog conjugate
• Drug resistant HIV
• Anti‐retrovirus drug conjugates

Acknowledgments

This manuscript is dedicated to a colleague, Dr. Leroy B. Townsend, for his inspiration and dedicated role as a collaborator in several scientific publications jointly made with one of us (L.S.K) over the span of several years. The present research described in this manuscript was funded in part by NCI grant CA 12197 awarded to the Comprehensive Cancer Center of Wake Forest University Health Sciences, the Cell Culture and Virus Vector Core Laboratory, Kucera Pharmaceutical Company, Winston‐Salem, NC 27101 and the North Carolina Small Business & Technology Development Center, State Headquarters, Raleigh, NC 27601.

Notes

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.