title: Small-molecule inhibition of human immunodeficiency virus type 1 replication by targeting the interaction between Vif and ElonginC.
abstract: The HIV-1 viral infectivity factor (Vif) protein is essential for viral replication. Vif recruits cellular ElonginB/C-Cullin5 E3 ubiquitin ligase to target the host antiviral protein APOBEC3G (A3G) for proteasomal degradation. In the absence of Vif, A3G is packaged into budding HIV-1 virions and introduces multiple mutations in the newly synthesized minus-strand viral DNA to restrict virus replication. Thus, the A3G-Vif-E3 complex represents an attractive target for development of novel anti-HIV drugs. In this study, we identified a potent small molecular compound (VEC-5) by virtual screening and validated its anti-Vif activity through biochemical analysis. We show that VEC-5 inhibits virus replication only in A3G-positive cells. Treatment with VEC-5 increased cellular A3G levels when Vif was coexpressed and enhanced A3G incorporation into HIV-1 virions to reduce viral infectivity. Coimmunoprecipitation and computational analysis further attributed the anti-Vif activity of VEC-5 to the inhibition of Vif from direct binding to the ElonginC protein. These findings support the notion that suppressing Vif function can liberate A3G to carry out its antiviral activity and demonstrate that regulation of the Vif-ElonginC interaction is a novel target for small-molecule inhibitors of HIV-1.
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, Changchun, Jilin Province, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zuo
authors.forename: Donglai
authors.initials: D
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wang
authors.forename: Jiawen
authors.initials: J
authors.lastname: Wang
authors.forename: Mingyu
authors.initials: M
authors.lastname: Lv
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Wu
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Jin
authors.forename: Liangren
authors.initials: L
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Xianghui
authors.initials: X
authors.lastname: Yu
mesh_terms: D000071480:APOBEC-3G Deaminase; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D000075065:Elongin; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D000075065:Elongin; D054852:Small Molecule Libraries; D014157:Transcription Factors; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase