Development of Antiviral Therapy of HIV-1 Infection

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

In the period to cover the present Annual Report, we explored imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors and designed, synthesized, and conducted protein X-ray structural studies, and biological evaluation (Ghosh & Mitsuya, ChemMedChem 2023). These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2' ligand exhibited the most potent antiviral activity. In other area, we established a multi-class-drug-resistant HIV-1 variant (HIVKGD) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN-strand-transfer-inhibitors (INSTIs). HIVKGD was found extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC50 of 130 femtomolar. When cells were infected with HIVKGD's IN-gene-containing recombinant-HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR-circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142 (Aoki & Mitsuya, Sci Adv 2023). The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.