In vitro anti-HIV-1 activity of sn-2-substituted 1-O-octadecyl-sn-glycero-3-phosphonoformate analogues and synergy with zidovudine Journal Article


Authors: Hostetler, K. Y.; Hammond, J. L.; Kini, G. D.; Hostetler, S. E.; Beadle, J. R.; Aldern, K. A.; Chou, T. C.; Richman, D. D.; Mellors, J. W.
Article Title: In vitro anti-HIV-1 activity of sn-2-substituted 1-O-octadecyl-sn-glycero-3-phosphonoformate analogues and synergy with zidovudine
Abstract: Monoalkyl ether lipid analogues of foscarnet (phosphonoformate, PFA) exhibit substantially greater in vitro antiviral activity than unmodified PFA against human immunodeficiency virus type 1 (HIV-1). Our previous studies indicate that the length of the alkyl chain must be 14-22 carbons for optimal antiviral activity. To further evaluate the structure-activity relationship, we prepared 1-O-octadecyl-sn-glycerol analogues of PFA with various substitutions at the sn-2 position of glycerol and determined the effect of structure on in vitro antiviral activity and selectivity against HIV-1 in MT-2 and CD4-expressing HeLa cells (HT4-6C). We also studied combinations of zidovudine with PFA, 1-O-octadecyl-2-O-methyl-sn-glycero-3-PFA, or 1-O-octadecyl-sn-glycero-3-PFA and calculated their combination index values against HIV-1 in HT4-6C cells. Alkyl substitutions of one to four carbons at the sn-2 position of glycerol showed optimal antiviral activity. Both alkyl ether lipid analogues were strongly synergistic with zidovudine over a wide range of drug ratios and concentrations. 1-O-octadecyl-sn-glycerol analogues of PFA have selective antiviral properties and warrant further evaluation as potential antiretroviral drugs.
Keywords: controlled study; unclassified drug; human cell; drug potentiation; hela cell; hela cells; drug selectivity; structure activity relation; drug synergism; cd4 antigen; virus replication; drug combinations; foscarnet; liposomes; drug carriers; antiviral activity; human immunodeficiency virus 1; hiv-1; zidovudine; carbon; antiviral agents; alkyl group; prodrugs; aids; glycerol; synergy; plaque assay; combination index; humans; human; priority journal; article; ether lipids; human immunodeficiency virus type 1; phosphonoformate; foscarnet derivative; octadecyl sn glycero 3 phosphonoformate analogue
Journal Title: Antiviral Chemistry and Chemotherapy
Volume: 11
Issue: 3
ISSN: 0956-3202
Publisher: Sage Publications  
Date Published: 2000-06-01
Start Page: 213
End Page: 219
Language: English
PUBMED: 10901292
PROVIDER: scopus
DOI: 10.1177/095632020001100304
DOI/URL:
Notes: Export Date: 18 November 2015 -- Source: Scopus
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MSK Authors
  1. Ting-Chao Chou
    234 Chou