Antiviral activities of nucleotide heterodimers against human immunodeficiency virus type 1 in vitro

Abstract Nucleotide heterodimers were synthesized and examined for their inhibitory effects on the replication of human immunodeficiency virus type 1 (HIV-1), including HIV-1 reverse transcriptase (RT) inhibitor-resistant mutants. 3′-Azido-3′-deoxythymidilyl-(5′)-phospho-(5′)-6-[(3′,5′-dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]uracil (AZT- P -E-HEPU-dM 3′-azido-3′-deoxythymidilyl-(5′)-phospho-(5′)-2′,3′-dideoxyinosine (AZT- P -ddI) proved to be highly potent and selective inhibitors of HIV-1 (III B strain) in MT-4 cells. The mechanism of inhibition by these heterodimers may be attributed to their degradation and the formation of each constituent. AZT- P -E-HEPU-dM was also markedly inhibitory to an AZT-resistant mutant ( HIV -1- III B AZT ) and an E-HEPU-dM-resistant mutant (HIV-1-III B–R ). However, AZT- P -ddI was found to have a less inhibitory effect on HIV -1- III B AZT than on HIV-1-III B . The heterodimers of (5′,5′) AZT and ribavirin (AZT- P -Ribavirin) and (5′,5′) ddI and ribavirin (ddI- P -Ribavirin) were also synthesized: AZT-P-Ribavirin inhibited HIV-1 replication, but ddI- P -Ribarvirin did not.