HTS-guided discovery of a novel plant-derived compound with retinal protective activity

Abstract Clinical translation of phytocompounds for antioxidant neuroprotection in Age-Related Macular Degeneration has had limited success due to the low bioavailability of these compounds in the retina. We carry out here a screen for more efficacious plant compounds that can specifically protect the metabolically fragile cone photoreceptor. 800 plant extracts were screened on chick cone culture to distill one phytocompound that achieved a 4.5-fold increase in cone survival rates with a notable increase in cone neurite outgrowth. This novel compound is structurally related to members of the class of acetogenins, which are the most potent Complex I inhibitors known, causing a decrease in mitochondrial membrane potential. The compound described here does not impact mitochondrial membrane potential at a range of tested doses, potentially due to the unique structure of its terminal γ-lactone moiety. Instead we show the compound can boost glycolysis in the cone photoreceptor through direct or indirect effects on the activity of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2 (PFKFB2). In this way the compound can prevent an induced atrophy in pig retinal explants and shows potential for future clinical translation. The phytochemical tropical library as described here may be of increasing value in future high-throughput screens for neuroprotective compounds.