Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the US. Age-dependent accumulation of cytotoxic lipofuscin in the retina matches the age-related increase in dry AMD prevalence implicating lipofuscin as a significant factor in pathogenesis of dry AMD. Enhanced buildup of retinal lipofuscin is the sole cause of Stargardt’s disease, a genetic form of untreatable macular degeneration. The major cytotoxic components of retinal lipofuscin are pyridinium bisretinoids. In addition to direct toxicity, bisretinoids induce complement system dysregulation and inflammasome activation in the retina. Biosynthesis of cytotoxic lipofuscin bisretinoids depends on the influx of retinol from serum to the retina which is mediated by serum Retinol-Binding Protein 4 (RBP4). Partial pharmacological reduction of serum retinol was suggested as a therapeutic approach to dry AMD and Stargardt’s disease treatment. Serum retinol is maintained in circulation in a complex with RBP4 and transthyretin (TTR). Without interacting with TTR, RBP4-retinol is rapidly cleared due to glomerular filtration. Retinol binding to RBP4 is required for the formation of the RBP4-TTR complex. We previously showed that selective RBP4 antagonists are capable of displacing retinol from RBP4, which leads to the disruption of the RBP4-TTR complex, reduction in serum retinol and inhibition of lipofuscin bisretinoid synthesis. However, selective RBP4 antagonists would release the unliganded TTR tetramer from the circulating RBP4-TTR complex which may facilitate TTR aggregation in susceptible individuals thus promoting TTR amyloidogenic diseases. Selective RBP4 antagonists may be counter-indicated for a significant number of dry AMD patients who may be prone to developing transthyretin amyloidosis (ATTR). Senile systemic amyloidosis (SSA) affects approximately 25% of patients over the age of 80 and is derived from aggregation of wild-type TTR. Based on the high population frequency of SSA and dry AMD significant comorbidity between the two conditions is expected. It is known that certain TTR ligands can act as kinetic tetramer stabilizers capable of inhibiting TTR amyloid formation. In a prior grant period we developed a novel class of bisretinoid-reducing compounds that comprises a group of bispecific RBP4/TTR ligands. The new class lacks a potential liability of selective RBP4 antagonists as these compounds can act as kinetic stabilizers of released TTR. An advanced bispecific analogue that we identified during a previous grant period will undergo a formal pre-clinical characterization required for its transitioning to the clinical stage of development (Aim 1). Our additional objective will be identification of the next generation of structurally diverse bispecific agents with significantly improved potency against both targets and optimal drug-like characteristics (Aim 2). Our third major objective will be using a co-drug strategy for developing novel therapies for m...