McAnally, DanielleSiddiquee, KhandakerGomaa, AhmedSzabo, AndrasVasile, StefanMaloney, Patrick R.Divlianska, Daniela B.Peddibhotla, SatyamaheshwarMorfa, Camilo J.Hershberger, PaulFalter, RebeccaWilliamson, RobertTerry, David B.Farjo, RafalPinkerton, Anthony B.Qi, XiapingQuigley, JudithBoulton, Michael E.Grant, Maria B.Smith, Layton H.2019-05-022019-05-022018-09-12McAnally, D., Siddiquee, K., Gomaa, A., Szabo, A., Vasile, S., Maloney, P. R., … Smith, L. H. (2018). Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. PloS one, 13(9), e0202436. doi:10.1371/journal.pone.0202436https://hdl.handle.net/1805/19069Neovascularization 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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesAminoquinolinesAngiogenesis inhibitorsAntimalarialsApelin receptorsChoroidal neovascularizationRetinal neovascularizationSmall molecule librariesVascular endothelial growth factor AArticle