Author:

Keywords:

Acyclovir, Anti-HIV Agents, Antiviral Agents, Cell Line, Dideoxynucleosides, Drug Design, Drug Evaluation, Preclinical, HIV, Humans, Microbial Sensitivity Tests, Molecular Structure, Moloney murine sarcoma virus, Prodrugs, Simplexvirus, Virus Replication, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Pharmacology & Pharmacy, Virology, cycloSal prodrugs, herpes simplex virus, guanosine analogues, PHOSPHATE-PROTECTING GROUPS, HERPES-SIMPLEX VIRUS, ANTI-HIV EFFICACY, PHOSPHORAMIDATE DERIVATIVES, INTRACELLULAR DELIVERY, NUCLEOSIDE MONOPHOSPHATES, DNA-POLYMERASES, PRONUCLEOTIDES, NUCLEOTIDES, METABOLISM, 0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1117 Public Health and Health Services, 3404 Medicinal and biomolecular chemistry

Abstract:

The cyclosaligenyl (cycloSal) derivatives of the monophosphates of three acyclic or carbocyclic guanosine analogues, for example, acyclovir (ACV), carbovir (CBV) and abacavir (ABC), were investigated for their activity against retrovirus (HIV, Moloney sarcoma virus) and herpes simplex virus (HSV) activity in cell culture. The extent of the antiviral potency of the prodrugs depended on the nature of the nucleoside, the substituent on the cycloSal moiety and the virus investigated. Most notably, and unlike the parent compound ACV, cycloSal-ACV monophosphate (MP) prodrugs retained pronounced activity against ACV-resistant (thymidine kinase-deficient) HSV-1 and also gained anti-HIV activity. While the cycloSal-CBVMP prodrugs did not show enhanced activity compared with the parent compound CBV, the cycloSal-ABCMP prodrugs afforded markedly increased potency against both HSV and HIV. Our data indicate that the cycloSal prodrug approach can be useful to deliver directly the MP derivatives of nucleoside analogues into the intact, virus-infected cells, thus improving and extending the antiviral potency and spectrum of the drugs against retro- and herpesvirus strains.