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 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

Discovery of a Plasmodium falciparum Glucose-6-phosphate Dehydrogenase 6‑phosphogluconolactonase Inhibitor (<i>R</i>,<i>Z</i>)‑<i>N</i>‑((1-Ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro‑2<i>H</i>‑benzo[<i>b</i>][1,4]thiazine-6-carboxamide (ML276) That Reduces Parasite Growth in Vitro

A high-throughput screen of the NIH’s MLSMR collection of ∼340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6-phosphate dehydrogenase (<i>Pf</i>G6PD). <i>Pf</i>G6PD is important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue. The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first, rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In P. falciparum, the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (<i>Pf</i>GluPho) catalyzes the first two steps of the PPP. Because P. falciparum and infected host red blood cells rely on accelerated glucose flux, they depend on the G6PD activity of <i>Pf</i>GluPho. The lead compound identified from this effort, (<i>R</i>,<i>Z</i>)-<i>N</i>-((1-ethylpyrrolidin-2-yl)­methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2<i>H</i>-benzo­[<i>b</i>]­[1,4]­thiazine-6-carboxamide, <b>11</b> (ML276), is a submicromolar inhibitor of <i>Pf</i>G6PD (IC₅₀ = 889 nM). It is completely selective for the enzyme’s human isoform, displays micromolar potency (IC₅₀ = 2.6 μM) against P. falciparum in culture, and has good drug-like properties, including high solubility and moderate microsomal stability. Studies testing the potential advantage of inhibiting <i>Pf</i>G6PD in vivo are in progress