Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization.

Autor: McAnally D; Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America.; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Siddiquee K; Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Gomaa A; Department of Ophthalmology, Indiana University School of Medicine Indianapolis, Indiana, United States of America., Szabo A; Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Vasile S; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Maloney PR; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Divlianska DB; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Peddibhotla S; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Morfa CJ; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Hershberger P; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Falter R; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Williamson R; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Terry DB; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America., Farjo R; EyeCRO LLC, Oklahoma City, Oklahoma, United States of America., Pinkerton AB; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America., Qi X; Department of Ophthalmology, Indiana University School of Medicine Indianapolis, Indiana, United States of America.; Department of Ophthalmology, University of Alabama, Birmingham, Alabama, United States of America., Quigley J; Department of Ophthalmology, Indiana University School of Medicine Indianapolis, Indiana, United States of America., Boulton ME; Department of Ophthalmology, Indiana University School of Medicine Indianapolis, Indiana, United States of America.; Department of Ophthalmology, University of Alabama, Birmingham, Alabama, United States of America., Grant MB; Department of Ophthalmology, Indiana University School of Medicine Indianapolis, Indiana, United States of America.; Department of Ophthalmology, University of Alabama, Birmingham, Alabama, United States of America., Smith LH; Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America.; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Sep 12; Vol. 13 (9), pp. e0202436. Date of Electronic Publication: 2018 Sep 12 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0202436
Abstrakt: 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.
Competing Interests: A patent covering the use of the compounds for pathological angiogenesis was submitted to the USPTO (“4-aminoquinoline compounds for the treatment of angiogenesis”; filed March 6, 2018; application number 62/639,291). This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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