Peptide Derivatives of Retinylamine Prevent Retinal Degeneration with Minimal Side Effects on Vision in Mice.

Safe and effective molecular therapeutics for prophylactic treatment of retinal degenerative diseases are greatly needed. Disruptions in the clearance of all--retinal (atRAL) by the visual (retinoid) cycle of the retina can lead to the accumulation of atRAL and its condensation products known to initiate progressive retinal dystrophy. Retinylamine (Ret-NH) and its analogues are known to be effective in lowering the concentration of atRAL within the eye and thus preventing retinal degeneration in mouse models of human retinopathies. Here, we chemically modified Ret-NH with amino acids and peptides to improve the stability and ocular bioavailability of the resulting derivatives and to minimize their side effects. Fourteen Ret-NH derivatives were synthesized and tested and . These derivatives exhibited structure-dependent therapeutic efficacy in preventing light-induced retinal degeneration in double-knockout mice, with the compounds containing glycine and/or -valine generally exhibiting greater protective effects than Ret-NH or other tested amino acid derivatives of Ret-NH. Ret-NH--valylglycine amide () exhibited good stability in storage; and effective uptake and prolonged retention in mouse eyes. readily formed a Schiff base with atRAL and did not inhibit RPE65 enzymatic activity. Administered by oral gavage, this retinoid also provided effective protection against light-induced retinal degeneration in mice. Notably, the treatment with had minimal effects on the regeneration of 11--retinal and recovery of retinal function. holds promise as a lead therapy for effective and safe treatment of human retinal degenerative diseases.