Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization

Danielle McAnally, Khandaker Siddiquee, Ahmed Gomaa, Andras Szabo, Stefan Vasile, Patrick R Maloney, Daniela B Divlianska, Satyamaheshwar Peddibhotla, Camilo J Morfa, Paul Hershberger, Rebecca Falter, Robert Williamson, David B Terry, Rafal Farjo, Anthony B Pinkerton, Xiaping Qi, Judith Quigley, Michael E Boulton, Maria B Grant and Layton H Smith

PLOS ONE, 2018, vol. 13, issue 9, 1-23

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0202436

DOI: 10.1371/journal.pone.0202436

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