Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization.
Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization.
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DOI：
10.1371/journal.pone.0202436
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Smith LH
中科院分区：
文献类型：
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作者：
McAnally D;Siddiquee K;Gomaa A;Szabo A;Vasile S;Maloney PR;Divlianska DB;Peddibhotla S;Morfa CJ;Hershberger P;Falter R;Williamson R;Terry DB;Farjo R;Pinkerton AB;Qi X;Quigley J;Boulton ME;Grant MB;Smith LH
Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic.
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影响因子：
3.9
作者：
Ehlken, C.;Jungmann, S.;Pielen, A.
通讯作者：
Pielen, A.
影响因子：
64.8
作者：
Goodman, OB;Krupnick, JG;Benovic, JL
通讯作者：
Benovic, JL
影响因子：
4.4
作者：
Irani, Yazad;Scotney, Pierre;Williams, Keryn A.
通讯作者：
Williams, Keryn A.
DOI：
10.1007/978-1-61779-909-9_8
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Bassoni, Daniel L;Jafri, Qumber;Wehrman, Tom S
通讯作者：
Wehrman, Tom S
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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