Small molecular compounds inhibit HIV-1 replication through specifically stabilizing APOBEC3G.
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.
Cen
Shan
S
Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing 100050, China.
Peng
Zong-Gen
ZG
Li
Xiao-Yu
XY
Li
Zhuo-Rong
ZR
Ma
Jing
J
Wang
Yue-Ming
YM
Fan
Bo
B
You
Xue-Fu
XF
Wang
Yu-Ping
YP
Liu
Fei
F
Shao
Rong-Guang
RG
Zhao
Li-Xun
LX
Yu
Liyan
L
Jiang
Jian-Dong
JD
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
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