Structure-based identification of small molecule compounds targeting cell cyclophilin A with anti-HIV-1 activity.
Cyclophilin A acts as protein folding chaperones and intracellular transports in many cellular processes. Previous studies have shown that cyclophilin A can interact with HIV-1 (human immunodeficiency virus type 1) gag protein and enhance viral infectivity. Many cyclophilin A inhibitors such as cyclosporin A can inhibit HIV-1 replication in vitro. Here, we report a structure-based identification of novel non-peptidic cyclophilin A inhibitors as anti-HIV lead compounds. Following a computer-aided virtual screening and subsequent surface plasmon resonance (SPR) analysis, 12 low molecular weight cyclophilin A ligands were selected for further evaluation of their in vitro inhibition of peptidyl-prolyl cis-trans isomerase (PPIase) activity of cyclophilin A and HIV-1 replication. Five of these compounds (FD5, FD8, FD9, FD10 and FD12) exhibited inhibition against both PPIase activity and HIV-1 infection. These active compounds will be used as leads for structure and activity relationship (SAR) and optimization studies in order to design more effective anti-HIV-1 therapeutics, and as probes for investigating the effect of cyclophilins on HIV-1 replication.
Chen
Shuai
S
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, People's Republic of China.
Zhao
Xuemei
X
Tan
Jinzhi
J
Lu
Hong
H
Qi
Zhi
Z
Huang
Qiang
Q
Zeng
Xianzhuo
X
Zhang
Mingjun
M
Jiang
Shibo
S
Jiang
Hualiang
H
Yu
Long
L
D019380:Anti-HIV Agents / Q000494:pharmacology*; D021984:Cyclophilin A / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors*; D020349:Surface Plasmon Resonance; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D016572:Cyclosporine; D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase