Department of Biomedical Engineering, School of Engineering, Case Western Reserve University, Cleveland, Ohio 44106, United States.
Center for Translation Vision Research, Gavin Herbert Eye Institute, Departments of Ophthalmology, Physiology & Biophysics, and Chemistry, University of California, Irvine, California 92697, United States.
Bioconjug Chem. 2021 Mar 17;32(3):572-583. doi: 10.1021/acs.bioconjchem.1c00043. Epub 2021 Mar 7.
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.
安全有效的分子疗法对于视网膜退行性疾病的预防治疗具有重要意义。视网膜视觉（类视黄醇）循环中对全-视网膜（atRAL）的清除障碍可导致 atRAL 的积累及其缩合产物，已知其可引发进行性视网膜营养不良。视黄胺（Ret-NH）及其类似物已被证明可有效降低眼内 atRAL 的浓度，从而预防人类视网膜病变小鼠模型中的视网膜变性。在这里，我们用氨基酸和肽对 Ret-NH 进行了化学修饰，以提高所得衍生物的稳定性和眼部生物利用度，并最大程度地减少其副作用。合成并测试了 14 种 Ret-NH 衍生物，其中，含有甘氨酸和/或缬氨酸的化合物通常比 Ret-NH 或其他测试的 Ret-NH 氨基酸衍生物具有更大的保护作用。Ret-NH-缬氨酰甘氨酸酰胺（）在储存中表现出良好的稳定性；并且在小鼠眼中具有有效的摄取和延长保留。它容易与 atRAL 形成席夫碱，并且不抑制 RPE65 酶活性。通过口服灌胃给药，这种类视黄醇还能有效预防光诱导的 小鼠视网膜变性。值得注意的是，用 治疗对 11-视黄醇的再生和视网膜功能的恢复影响最小。作为一种有效的治疗方法，具有治疗人类视网膜退行性疾病的潜力。
