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 |
