Uncovering novel drugs that restore vision by combining biological and computational drug discovery processes

Retinal degeneration is the leading cause of blindness in the industrialised world1 and is characterised by progressive loss of the light sensing cells, photoreceptors, in the retina. Retinal degeneration occurs in both inherited retinal degenerations (IRD) and age-related macular degeneration (AMD). Limited therapies are available for both conditions and there is a pressing need to uncover novel therapies to rescue/preserve vision. With the advent of computational technology and new screening techniques, novel compounds restoring vision can be uncovered by combining computational and phenotypic drug discovery methodologies. Here, I present two complementary workflows to identify compounds rescuing vision. Firstly, ligand-based virtual screening was used to uncover 3D analogues of 7,8-DHF using Cresset Ltd, Blaze’s software. The second workflow utilised orthogonal pooling to screen 720 compounds from the Chembridge DIVERSet™ compound library for hit compounds. Screening for both workflows was conducted using the optokinetic response assay in the atp6voe1-/- zebrafish model of inherited blindness. Three hit compounds were discovered to rescue vision. Compounds UCD-OPGG-A2 and UCD-OPGG-B15 were identified as 3D analogues of 7,8-DHF restoring vision. Compound UCD-OPGG-3E was uncovered during the randomised library screen. RT-qPCR of 3E and A2 did not confirm alterations in inflammatory or oxidative stress related genes in atp6voe1-/- after drug treatment. Light microscopy analysis suggests 3E may reduce cell death within the ciliary marginal zone of atp6voe1-/- larvae. Tolerability studies performed in collaboration with Experimentica Ltd, indicate that intravitreal injections of A2 and 3E are tolerated in mice. In conclusion, I helped develop two complementary workflows to efficiently detect compounds rescuing vision. Although additional experimentation is needed, compounds A2 and 3E are promising starting points for the discovery of novel compounds to restore vision.