Title: 4 -C-Substituted-2 -Deoxynucleosides A Family of Antiretroviral Agents Which are Potent Against Drug-Resistant HIV Variants.
Volume: 1
Issue: 1
Author(s): Hiroshi Ohrui and Hiroaki Mitsuya
Affiliation:
Keywords:
C Substituted Deoxynucleosides, Antiretroviral Agents, Drug Resistant HIV Variants, C substituted deoxynucleosides SdNs, azido deoxythymidine AZT, Otriphosphates, anti HIV nucleosides, SYNTHESIS, ENZYMICCATABOLISM, azido deoxythymidine, dideoxyinosine
Abstract: In the past years, a variety of 4-C-substituted - 2- deoxynucleosides (4SdNs) were designed, synthesized, and examined as potential therapeutics against human immunodeficiency virus (HIV) infection and certain such analogues proved to exert potent activity against HIV-1 in vitro. Unlike currently available nucleoside reverse transcriptase (RT) inhibitors such as 3-azido-3-deoxythymidine (AZT), which have the 2,3-dideoxy configuration and thereby cause DNA chain termination in the elongating proviral DNA, 4SdNs do retain the 3-a-OH moiety but also appear to work against retrovirus as proviral DNA chain terminators. Several 4SdNs have been shown to be active against various laboratory and clinical HIV-1 strains including known drug-resistant HIV-1 variants. Among such 4SdNs is 4-azido-2-deoxythymidine (4-AZT) which exerts potent antiviral activity against wild type and AZT-resistant clinical HIV strains. More anti-HIV 4SdNs have recently been reported including 4-ethynylthymidine, 4-ethynyl-2-deoxy-D-ribofuranosyl-2,6-diaminopurine (4-E-dDAP), 4-ethyny1- 2-deoxyguanosine (4-E-dG) and 4-ethynyl-2-deoxyadenosine (4-E-dA). The latter three analogues are highly potent against HIV-1 and HIV-2 with EC50 values ranging from 0.0003 to 0.01 mM and have favorable cytotoxicity profiles with selective index (SI) values ranging from 975 to 2600. These 4-ethynyl-2-deoxynucleosides also exert potent activity against all known drug-resistant HIV-1 variants including the multi-dideoxynucleoside-resistant HIV and the variants with the 6-base pair inserts. Some of these compounds have favorable pharmacological properties and further development as potential therapeutics against HIV-1 infection is warranted.
