Synthesis and Antiviral Evaluation of 1-O-Hexadecylpropanediol-3-P-acyclovir: Efficacy Against HSV-1 Infection in Mice

• Published in: Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2000-01, Vol.19 (1-2), p.471-479
• Main Authors: Beadle, James R., Kini, Ganesh D., Aldern, Kathy A., Gardner, Michael F., Wright, Kristine N., Rybak, Rachel J., Kern, Earl R., Hostetler, Karl Y.
• Format: Article
• Language: English
• Subjects: Acyclovir - administration & dosage; Acyclovir - analogs & derivatives; Acyclovir - chemical synthesis; Acyclovir - pharmacology; Administration, Oral; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Cytomegalovirus - drug effects; Encephalitis, Herpes Simplex - drug therapy; Female; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - genetics; Mice; Mice, Inbred BALB C; Mutation; Prodrugs - administration & dosage; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Thymidine Kinase - genetics
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1080/15257770008033022

We synthesized, 1-O-hexadecylpropanediol-3-P-acyclovir, an orally bioavailable lipid prodrug of acyclovir and evaluated it for in vitro and in vivo activity against herpes simplex virus infections. Although 1-O-hexadecylpropanediol-3-P-acyclovir was less active in vitro than acyclovir, on a molar basis it was 2.4 times more active orally in preventing mortality from acute HSV-1 infection in mice. In vitro, 1-O-hexadecylpropanediol-3-P-acyclovir was also more active than acyclovir in a thymidine kinase negative mutant strain of HSV-1 (DM21) and had somewhat higher activity in cytomegalovirus infection in vitro due to it's ability to bypass thymidine kinase.