齐多夫定
赫拉
乙醚
体外
甘油
烷基
立体化学
化学
生物活性
选择性
人类免疫缺陷病毒(HIV)
生物化学
有机化学
病毒学
生物
病毒性疾病
催化作用
作者
Karl Y. Hostetler,Jennifer Hammond,Ganesh D. Kini,Saskia E Hostetler,James R. Beadle,Kathy A. Aldern,Ting‐Chao Chou,Douglas D. Richman,John W. Mellors
标识
DOI:10.1177/095632020001100304
摘要
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.
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