Petrukhin, K. | bioRxiv Science

bioRxiv2026

A non-retinoid triazolopyrimidine RBP4 antagonist for the treatment of Stargardt disease

Stargardt disease is a juvenile-onset retinal dystrophy characterized by the buildup of cytotoxic lipofuscin deposits in the retinal pigment epithelium (RPE), leading to photoreceptor degeneration and eventual blindness. Currently, there are no FDA-approved treatments for Stargardt disease. Bisretinoids, byproducts of the visual cycle, are the major cytotoxic components of the lipofuscin deposits, and bisretinoid synthesis relies on the traffic of retinol from the bloodstream to the retina. Selective targeting of the key retinol transporter, Retinol-Binding Protein 4 (RBP4), offers an appealing strategy for halting the buildup of lipofuscin in the RPE and arresting the progression of Stargardt disease. Retinol delivery depends on RBP4 interaction with another serum protein, Transthyretin (TTR). We previously reported several libraries of RBP4 antagonists that effectively blocked the association of the TTR-RBP4-retinol tertiary complex, thereby lowering the overall retinol load in the retina; however, some chemotypes displayed off-target activity that warranted further optimization. Here, we report the pharmacological characterization of AKR-XI-85 and its analogs as promising non-retinoid small-molecule RBP4 antagonists. AKR-XI-85 displayed excellent in vitro and in vivo efficacy and desirable pharmacokinetic properties without any limiting off-target activity. In Abca4-/- mice, chronic dosing of the compound induced a prolonged reduction in serum RBP4 levels and achieved a dramatic, 70 % reduction in the accumulation of A2E, a critical component of toxic lipofuscin. As such, AKR-XI-85 may be an attractive drug candidate for the treatment of Stargardt disease and other lipofuscin-dependent retinopathies.

pharmacology and toxicology↗

bioRxiv2026

Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in elderly individuals for which no effective treatments are currently available. The photoreceptor loss in dry AMD is secondary to the demise of the retinal pigment epithelium (RPE) cells. The accumulation of extracellular deposits, known as drusen, resulting in part from deficient lysosomal and autophagosomal degradation, is a key feature of dry AMD pathogenesis. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains proteostasis by targeting specific cytosolic proteins for lysosomal translocation and degradation. LAMP2A (lysosome-associated membrane protein 2A) functions as the key lysosomal receptor required for CMA. Using Lamp2a knockout mouse, we show that selective CMA dysfunction recapitulates AMD-like pathologies, including sub-RPE lipid and protein deposits, RPE atrophy, Bruchs membrane thickening, and impaired autophagic activity. Furthermore, we identify large-conductance Ca{superscript 2}-activated K (BK) channels as a therapeutic target for restoring autophagic activity. Mechanistically, pharmacological activation of BK channels with the small-molecule agonist GLA-1-1 enhances macroautophagy and stimulates autophagic flux by promoting autophagosome-lysosome fusion. Importantly, oral administration of GLA-1-1 in markedly attenuates structural, functional, and molecular retinal abnormalities in Lamp2a-deficient mice, suggesting that pharmacological activation of macroautophagy through facilitating autophagosome-lysosome fusion can partially compensate for CMA deficiency. Together, these findings demonstrate that pharmacological activation of macroautophagy can ameliorate the retinal phenotype resulting from CMA dysfunction and support BK channel activation by GLA-1-1 as a promising therapeutic strategy for dry AMD.

pharmacology and toxicology↗