Nucleoside-ATTEC Conjugates for Targeting Inhibition of HIV Replication and Infection.
J Med Chem 2026 Apr 23; 69(8):8807-8817.

Abstract

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Liao XLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
Zhang KNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, P. R. China.
Wang CNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, P. R. China.
Liu MLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
Ren J0000-0002-7506-627XLaboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
Qu X0000-0003-2868-3205Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.

MeSH

HumansVirus ReplicationAnti-HIV AgentsHIV-1NucleosidesHIV InfectionsStructure-Activity RelationshipHIV Reverse TranscriptaseReverse Transcriptase InhibitorsZidovudineCoumarins

Pub Type(s)

Journal Article

Language

eng

PubMed ID

41919317