Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization
| Autor: | Anthony B. Pinkerton, Maria B. Grant, Patrick R. Maloney, Andras Szabo, Danielle McAnally, Satyamaheshwar Peddibhotla, Xiaping Qi, Rafal Farjo, Robert Williamson, Khandaker Siddiquee, Camilo J. Morfa, Judith Quigley, Michael E. Boulton, Paul Hershberger, Ahmed Gomaa, Layton H. Smith, Rebecca Falter, Daniela B. Divlianska, David B. Terry, Stefan Vasile |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A genetic structures Angiogenesis lcsh:Medicine Angiogenesis Inhibitors Amodiaquine Pharmacology Retinal Neovascularization Cell Line Neovascularization Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Antimalarials Mice medicine Animals Humans Tissue Distribution lcsh:Science Cell Proliferation Tube formation Apelin Receptors Multidisciplinary business.industry Lasers lcsh:R Drug Repositioning Diabetic retinopathy medicine.disease eye diseases Choroidal Neovascularization Apelin Vascular endothelial growth factor Mice Inbred C57BL Disease Models Animal 030104 developmental biology Choroidal neovascularization chemistry Aminoquinolines lcsh:Q Female sense organs medicine.symptom business medicine.drug |
| Zdroj: | PLoS ONE, Vol 13, Iss 9, p e0202436 (2018) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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