Abstract
HIV remains a health challenge worldwide, partly because of the continued development of resistance to drugs. Therefore, it is urgent to find new HIV inhibitors and targets. Apolipoprotein B mRNA-editing catalytic polypeptide-like 3 family members (APOBEC3) are important host restriction factors that inhibit HIV-1 replication by their cytidine deaminase activity. HIV-1 viral infectivity factor (Vif) promotes proteasomal degradation of APOBEC3 proteins by recruiting the E3 ubiquitin ligase complex, in which core-binding factor β (CBFβ) is a necessary molecular chaperone. Interrupting the interaction between Vif and CBFβ can release APOBEC3 proteins to inhibit HIV-1 replication and may be useful for developing new drug targets for HIV-1. In this study, we identified a potent small molecule inhibitor CBFβ/Vif-3 (CV-3) of HIV-1 replication by employing structure-based virtual screening using the crystal structure of Vif and CBFβ (PDB: 4N9F) and validated CV-3's antiviral activity. We found that CV-3 specifically inhibited HIV-1 replication (IC50 = 8.16 µm; 50% cytotoxic concentration >100 µm) in nonpermissive lymphocytes. Furthermore, CV-3 treatment rescued APOBEC3 family members (human APOBEC3G (hA3G), hA3C, and hA3F) in the presence of Vif and enabled hA3G packaging into HIV-1 virions, which resulted in Gly-to-Ala hypermutations in viral genomes. Finally, we used FRET to demonstrate that CV-3 inhibited the interaction between Vif and CBFβ by simultaneously forming hydrogen bonds with residues Gln-67, Ile-102, and Arg-131 of CBFβ. These findings demonstrate that CV-3 can effectively inhibit HIV-1 by blocking the interaction between Vif and CBFβ and that this interaction can serve as a new target for developing HIV-1 inhibitors.
Highlights
Host restriction factors play an important role in innate immune responses that protect cells from viral pathogens such as HIV [1, 2]
By employing virtual screening based on the crystal structure of the viral infectivity factor (Vif)-corebinding factor beta (CBFb) complex (PDB: 4N9F), we identified a small molecule compound called CV-3 that inhibited the interaction between Vif and CBFb
The results indicate that small molecule compound CV-3 can release APOBEC3 proteins by blocking the Vif-CBFb interaction to achieve an antiviral effect; it could be used as a potential novel anti-HIV-1 drug candidate
Summary
Host restriction factors play an important role in innate immune responses that protect cells from viral pathogens such as HIV [1, 2]. Various inhibitors targeting Vif function have been identified, but no small molecule compounds targeting Vif-CBFb have been reported [34]. There are some small molecule inhibitors that target the Vif-EloC interaction, including VEC-5 [39], ZBMA-1 [40], analogs 12c/13a [41], and Zif-15 [42]. We aimed to identify small molecule inhibitors that interrupt the Vif-CBFb interaction, which can release APOBEC3s and Vif-hijacking proteins in the E3-ubiquitin ligase complex, such as Cul, EloB, and EloC. By employing virtual screening based on the crystal structure of the Vif-CBFb complex (PDB: 4N9F), we identified a small molecule compound called CV-3 that inhibited the interaction between Vif and CBFb. CV-3 was found to inhibit HIV-1 replication (IC50 = 8.16 mM) and have a low cytotoxicity (50% cytotoxic concentration (CC50) . In the “calculate binding energy” protocol, “in situ ligand minimization” and “ligand conformational entropy” were selected as “true.” “Implicit solvent model” was selected as “distance-dependent dielectrics.”
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