Zaluski Jordan, Bassetto Marco, Kiser Philip D, Tochtrop Gregory P
Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA.
Department of Physiology and Biophysics, School of Medicine, University of California- Irvine, Irvine, CA, 92697, USA; Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, School of Medicine, University of California- Irvine, Irvine, CA, 92697, USA; Research Service, VA Long Beach Healthcare System, Long Beach, CA, 90822, USA.
Prog Retin Eye Res. 2025 May;106:101360. doi: 10.1016/j.preteyeres.2025.101360. Epub 2025 Apr 23.
The visual cycle is a metabolic pathway that enables continuous vision by regenerating the 11-cis-retinal chromophore for photoreceptors opsins. Although integral to normal visual function, the flux of retinoids through this cycle can contribute to a range of retinal pathologies, including Stargardt disease, age-related macular degeneration, and diabetic retinopathy. In such conditions, intermediates and byproducts of the visual cycle, such as bisretinoid components of lipofuscin, can accumulate, concomitant with cellular damage and eventual photoreceptor loss. This has inspired efforts to modulate the visual cycle, aiming to slow or prevent the formation of these toxic intermediates and thus preserve retinal structure and function. Over the past two decades, multiple strategies to modulate the visual cycle have emerged. These include both intrinsic approaches, targeting key enzymes, retinoid-binding proteins, or receptors within the pigment epithelium or photoreceptors (e.g., RPE65, CRBP1, and rhodopsin inhibitors/antagonists) and extrinsic strategies that indirectly alter retinoid availability within the retina (e.g., RBP4 antagonists). Many of these agents have shown promise in animal models of visual cycle-associated retinal diseases, reducing pathological changes, and improving retinal survival. Several have advanced into clinical studies, although none are currently FDA-approved. Challenges remain in optimizing drug specificity and duration of action while minimizing side effects such as nyctalopia. In this review, we comprehensively examine current and emerging visual cycle modulators, discuss their medicinal chemistry, mechanisms of action, efficacy in preclinical and clinical studies, and highlight future opportunities for drug discovery aimed at safely and effectively preserving vision through modulation of this biochemical pathway.
视觉循环是一种代谢途径，通过为光感受器视蛋白再生11-顺式视黄醛发色团来实现持续视觉。尽管对视功能正常至关重要，但类视黄醇通过该循环的通量可导致一系列视网膜病变，包括斯塔加特病、年龄相关性黄斑变性和糖尿病性视网膜病变。在这些情况下，视觉循环的中间体和副产物，如脂褐质的双视黄醛成分，会积累，同时伴有细胞损伤和最终的光感受器丧失。这激发了人们调节视觉循环的努力，旨在减缓或防止这些有毒中间体的形成，从而保护视网膜结构和功能。在过去二十年中，出现了多种调节视觉循环的策略。这些策略包括内在方法，即针对色素上皮或光感受器内的关键酶、类视黄醇结合蛋白或受体（如RPE65、CRBP1和视紫红质抑制剂/拮抗剂），以及间接改变视网膜内类视黄醇可用性的外在策略（如RBP4拮抗剂）。这些药物中的许多在视觉循环相关视网膜疾病的动物模型中显示出前景，减少了病理变化，提高了视网膜存活率。有几种药物已进入临床研究，尽管目前尚无一种获得美国食品药品监督管理局（FDA）批准。在优化药物特异性和作用持续时间的同时，将诸如夜盲等副作用降至最低方面，仍存在挑战。在这篇综述中，我们全面研究了当前和新兴的视觉循环调节剂，讨论了它们的药物化学、作用机制、临床前和临床研究中的疗效，并强调了通过调节这一生化途径安全有效地保护视力的药物发现的未来机会。
