Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization.
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 pati...
Main Authors: | , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2018-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC6135396?pdf=render |
id |
doaj-2711b08fb0d24cb796c83d996b6a93ad |
---|---|
record_format |
Article |
spelling |
doaj-2711b08fb0d24cb796c83d996b6a93ad2020-11-25T00:25:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01139e020243610.1371/journal.pone.0202436Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization.Danielle McAnallyKhandaker SiddiqueeAhmed GomaaAndras SzaboStefan VasilePatrick R MaloneyDaniela B DivlianskaSatyamaheshwar PeddibhotlaCamilo J MorfaPaul HershbergerRebecca FalterRobert WilliamsonDavid B TerryRafal FarjoAnthony B PinkertonXiaping QiJudith QuigleyMichael E BoultonMaria B GrantLayton H SmithNeovascularization 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.http://europepmc.org/articles/PMC6135396?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. PLoS ONE |
author_facet |
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 |
author_sort |
Danielle McAnally |
title |
Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. |
title_short |
Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. |
title_full |
Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. |
title_fullStr |
Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. |
title_full_unstemmed |
Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. |
title_sort |
repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2018-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC6135396?pdf=render |
work_keys_str_mv |
AT daniellemcanally repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT khandakersiddiquee repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT ahmedgomaa repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT andrasszabo repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT stefanvasile repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT patrickrmaloney repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT danielabdivlianska repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT satyamaheshwarpeddibhotla repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT camilojmorfa repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT paulhershberger repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT rebeccafalter repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT robertwilliamson repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT davidbterry repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT rafalfarjo repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT anthonybpinkerton repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT xiapingqi repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT judithquigley repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT michaeleboulton repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT mariabgrant repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization AT laytonhsmith repurposingantimalarialaminoquinolinesandrelatedcompoundsfortreatmentofretinalneovascularization |
_version_ |
1725348155326726144 |