PLoS ONE (Jan 2018)

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,
  • Layton H Smith

DOI
https://doi.org/10.1371/journal.pone.0202436
Journal volume & issue
Vol. 13, no. 9
p. e0202436

Abstract

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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.