title: Small molecular compounds inhibit HIV-1 replication through specifically stabilizing APOBEC3G.
abstract: APOBEC3G (hA3G) is a host inhibitor for human immunodeficiency virus, type 1 (HIV-1). However, HIV-1 Vif binds hA3G and induces its degradation. We have established a screening system to discover inhibitors that protect hA3G from Vif-mediated degradation. Through screening, compounds IMB-26 and IMB-35 were identified to be specific inhibitors for the degradation of hA3G by Vif. The inhibitors suppressed HIV-1 replication in hA3G-containing cells but not in those without hA3G. The anti-HIV effect correlated with the endogenous hA3G level. HIV-1 particles from hA3G(+) cells treated with IMB-26/35 contained a hA3G level higher than that from those without IMB-26/35 treatment and showed decreased infectivity. IMB-26/35 bound directly to the hA3G protein, suppressed Vif/hA3G interaction, and therefore protected hA3G from Vif-mediated degradation. The compounds were safe with an anti-HIV therapeutic index >200 in vitro. LD(50) of IMB-26 in mice was >1000 mg/kg (intraperitoneally). Therefore, IMB-26 and IMB-35 are novel anti-HIV leads working through specific stabilization of hA3G.
authors.affiliation: Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing 100050, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Cen
authors.forename: Zong-Gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Li
authors.forename: Zhuo-Rong
authors.initials: ZR
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Fan
authors.forename: Xue-Fu
authors.initials: XF
authors.lastname: You
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Rong-Guang
authors.initials: RG
authors.lastname: Shao
authors.forename: Li-Xun
authors.initials: LX
authors.lastname: Zhao
authors.forename: Liyan
authors.initials: L
authors.lastname: Yu
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000071480:APOBEC-3G Deaminase; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003564:Cytidine Deaminase / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D010957:Plasmids / Q000378:metabolism; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D054320:vif Gene Products, Human Immunodeficiency Virus; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; C496166:APOBEC3G protein, mouse; D003564:Cytidine Deaminase