title: 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 multidrug 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 microM 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 microM for INK-20 and 0.0005 and 0.33 microM 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.
authors.affiliation: Wake Forest University School of Medicine, Department of Microbiology and Immunology, Winston-Salem, North Carolina 27157-1064, USA. lkucera@wfubmc.edu
authors.forename: Louis S
authors.initials: LS
authors.lastname: Kucera
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Ishaq
authors.forename: Jan
authors.initials: J
authors.lastname: Hes
authors.forename: Nathan
authors.initials: N
authors.lastname: Iyer
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Fleming
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008314:Malonates / Q000737:chemistry; D010767:Phosphorylcholine / Q000737:chemistry*; D015215:Zidovudine / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D008314:Malonates; D010767:Phosphorylcholine; D015215:Zidovudine; C030290:malonic acid