AEGiS-06IAC: Antiretroviral effects of glycerophospholipid stereoisomers of AZT on HIV replication in HT4-6C cells.

6th International AIDS Conference

San Francisco, California, USA — June 20-23, 1990

Antiretroviral effects of glycerophospholipid stereoisomers of AZT on HIV replication in HT4-6C cells.

Int Conf AIDS 1990 Jun 20-23; 6:186 (abstract no. Th.A.265)
Kumar R, Richman DD, Hostetler KY; Vical Inc, San Diego, CA, USA

OBJECTIVE: Macrophages are an important target for anti-HIV therapies. We previously reported the synthesis of sn-3 phosphatidylAZT (pAZT), a phospholipid prodrug of azidothymidine (AZT, zidovudine) which was active in HIV-infected cells. pAZT can be targeted to macrophages in vivo. We wished to determine if the sn-1 derivative is also effective in HIV-infected cells since most of the cellular phospholipases are stereospecific for sn-3 phosphoglycerides.

METHODS: We synthesized sn-1, sn-3, and racemic dipalmitoylglycerophosphoAZT from the corresponding isopropylidene glycerols by coupling with AZT-monophosphate followed by deblocking and acylation of the hydroxyls of glycerol with palmitic anhydride. Lipid vesicles containing 10 mole % of the pAZTs were incubated with HT4-6C cells after infection with the LAV-1BRU strain of HIV in a plaque reduction assay.

RESULTS: sn-3 pAZT reduced plaque formation by 50% (ID50) at 2.1 uM versus 2.2 uM for the sn-1 derivative while racemic pAZT had an IC50 of 2.7 uM. None of these differences were statistically significant (n=3).

CONCLUSIONS: Contrary to expectations, the sn-1 and sn-3 derivatives of pAZT were equally effective in reducing HIV replication of HT4-6C cells. This is a surprising result since most cellular phospholipases are thought to be specific for the sn-3 glycerophospholipids. Intact pAZTs have no intrinsic activity against HIV reverse transcriptase (RT). Therefore, the sn-1 pAZT must be degraded in the cell by enzymatic processes which are still uncharacterized before being converted to AZT-triphosphate, the inhibitor of RT.

Keywords: AEGIS, Zidovudine, HIV, Virus Replication, Antiviral Agents, Glycerophospholipids, Thymine Nucleotides, Stereoisomerism, RNA-Directed DNA Polymerase, Reverse Transcriptase Inhibitors, Anti-HIV Agents, Phospholipids, Plaque Assay, Prodrugs, HIV Infections, 3'-azido-3'-deoxythymidine 5'-triphosphate, chemical synthesis, virology, ICA6

900620
ThA265