Old Target with New Vision: In Search of New Therapeutics for Diabetic Retinopathy by Selective Modulation of Aldose Reductase

Despite decades of investigation, Aldose Reductase (AR; AKR1B1) -an enzyme that plays a key role in the metabolism of glucose and other carbonyl compounds and whose hy-peractivity contributes to oxidative stress and vascular dysfunction- inhibitors have failed to translate into clinical application for Diabetic Retinopathy (DR). We argue that these failures might arise from non-selective inhibition, which does not consider AR’s dual roles in pathology but also in retinal health, as AR is also an important detoxifying enzyme for aldehydes produced during oxidative stress, and discuss the missing structural infor-mation, despite the over one hundred crystal structures of AR in complex with inhibitors. Our review bridges this gap by proposing how recent advances in structural biology, namely, fragment-based drug discovery and MicroED, provide novel ways of selectively modulating AR functions, offering advantages in the detection of weak, allosteric, or conformation-dependent binding events. Despite past challenges, we suggest that therapeutic targeting or finding new-generation inhibitors for AR will become more effective once we have a clearer understanding of AR’s requirements for selective inhi-bition of its pathological and physiological functions. By integrating fragment screening and structural biology, we outline a strategy to reinvigorate AR modulation as a viable retina-specific approach for managing DR first, although potentially relevant across multiple diabetic microvascular complications later.