Antiviral phospholipids. Anti-HIV drugs conjugated to the glycerobackbone of phospholipids.
Heteroatom fatty acid analogs of myristic acid containing oxygen or sulfur substituted for the alkyl methylene groups inhibit replication of the human immunodeficiency virus (HIV) in infected cells by acting as alternative substrates during the viral protein myristoylation event. In this class of compounds, 12-methoxydodecanoic acid is the most potent compound but is approximately 10(3)-fold less active than azidothymidine. The antiviral activity of 12-methoxydodecanoic acid can be enhanced > 40-fold by preparing L-alpha-phosphatidylethanolamine containing 12-methoxydodecanoic acid in both alkyl chains. In addition, the diacylated L-alpha-phosphatidylcholine analog containing 12-methoxydodecanoic acid in both alkyl chains (i) has a 15-fold better antiviral selectivity, (ii) is 7-fold more potent, and (iii) is 10-100-fold more synergistic with azidothymidine than 12-methoxydodecanoic acid. Because of potent synergism, the antiviral selectivity of the diacylated L-alpha-phosphatidylcholine analog is > 10(4) when coadministered with azidothymidine. Phospholipid conjugates are chiral at the C-2 carbon of the glycerol backbone and most interesting is the observation that both the D- and L-isomers of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, and phosphatidylserine have approximately equal antiviral activity. Phospholipase A2 stereospecifically hydrolyzes only the L isomer of phospholipids and similar activity for both the D- and L- phospholipid isomers suggests that phospholipase A2 is not the rate-limiting enzyme for release of the drugs in vivo.
Pidgeon
C
C
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907.
Markovich
R J
RJ
Liu
M D
MD
Holzer
T J
TJ
Novak
R M
RM
Keyer
K A
KA
D000998:Antiviral Agents / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D015195:Drug Design; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006207:Half-Life; D006801:Humans; D007536:Isomerism; D007848:Laurates / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D010743:Phospholipids / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D007848:Laurates; D010743:Phospholipids; D015215:Zidovudine; C067939:12-methoxydodecanoate; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase