Nucleoside-ATTEC Conjugates for Targeting Inhibition of HIV Replication and Infection

HIV-1 reverse transcriptase (RT) has been a key target for HIV treatment, and several RT inhibitors have been utilized in the clinic. However, RT inhibitors are incapable of eradicating reverse-transcribed DNA, and drug resistance has greatly compromised drug efficacy. Here, we have presented a nucleoside-autophagosome-tethering compound (ATTEC) aiming to inhibit HIV by inducing viral cDNA degradation during replication. 5,7-Dihydroxy-4-phenylcoumarin (DP) derivatives with varied linker lengths were designed and synthesized as LC3-binding ligands and further conjugated with 3'-azidothymidine (AZT) via a bioorthogonal click reaction to form nucleoside-ATTECs. After comparing and optimizing the linker length, our developed nucleoside-ATTEC can effectively inhibit HIV replication and infection in human cells without interfering with cell proliferation. Moreover, DP-AZT has been shown to have the capacity for the prolonged inhibition of HIV-1 replication. Therefore, this work provides a good example of developing a nucleoside-ATTEC approach to inhibit HIV replication and infection.