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Targeting Relevant HDACs to Support the Survival of Cone Photoreceptors in Inherited Retinal Diseases: Identification of a Potent Pharmacological Tool with In Vitro and In Vivo Efficacy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-04 , DOI: 10.1021/acs.jmedchem.4c00477 Gabriele Carullo 1 , Noemi Orsini 2, 3 , Ilaria Piano 4 , Luca Pozzetti 1 , Alessandro Papa 1 , Anna Fontana 1 , Debora Napoli 2, 3 , Francesca Corsi 4 , Beatrice Di Marco 2, 3 , Alessia Galante 4 , Ludovica Marotta 1 , Giovanna Panzeca 1 , Justine O'Brien 5 , Alicia Gomez Sanchez 5 , Harry Doherty 5 , Niamh Mahon 5 , Leni Clarke 5 , Chiara Contri 6 , Silvia Pasquini 7 , Beatrice Gorelli 8 , Simona Saponara 8 , Massimo Valoti 8 , Fabrizio Vincenzi 7 , Katia Varani 7 , Anna Ramunno 9 , Simone Brogi 4 , Stefania Butini 1 , Sandra Gemma 1 , Breandán N Kennedy 5 , Claudia Gargini 4 , Enrica Strettoi 2 , Giuseppe Campiani 1, 10
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-04 , DOI: 10.1021/acs.jmedchem.4c00477 Gabriele Carullo 1 , Noemi Orsini 2, 3 , Ilaria Piano 4 , Luca Pozzetti 1 , Alessandro Papa 1 , Anna Fontana 1 , Debora Napoli 2, 3 , Francesca Corsi 4 , Beatrice Di Marco 2, 3 , Alessia Galante 4 , Ludovica Marotta 1 , Giovanna Panzeca 1 , Justine O'Brien 5 , Alicia Gomez Sanchez 5 , Harry Doherty 5 , Niamh Mahon 5 , Leni Clarke 5 , Chiara Contri 6 , Silvia Pasquini 7 , Beatrice Gorelli 8 , Simona Saponara 8 , Massimo Valoti 8 , Fabrizio Vincenzi 7 , Katia Varani 7 , Anna Ramunno 9 , Simone Brogi 4 , Stefania Butini 1 , Sandra Gemma 1 , Breandán N Kennedy 5 , Claudia Gargini 4 , Enrica Strettoi 2 , Giuseppe Campiani 1, 10
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Inherited retinal diseases, which include retinitis pigmentosa, are a family of genetic disorders characterized by gradual rod-cone degeneration and vision loss, without effective pharmacological treatments. Experimental approaches aim to delay disease progression, supporting cones’ survival, crucial for human vision. Histone deacetylases (HDACs) mediate the activation of epigenetic and nonepigenetic pathways that modulate cone degeneration in RP mouse models. We developed new HDAC inhibitors (5a–p), typified by a tetrahydro-γ-carboline scaffold, characterized by high HDAC6 inhibition potency with balanced physicochemical properties for in vivo studies. Compound 5d (repistat, IC50 HDAC6 = 6.32 nM) increased the levels of acetylated α-tubulin compared to histone H3 in ARPE-19 and 661W cells. 5d promoted vision rescue in the atp6v0e1–/– zebrafish model of photoreceptor dysfunction. A single intravitreal injection of 5d in the rd10 mouse model of RP supported morphological and functional preservation of cone cells and maintenance of the retinal pigment epithelium array.
中文翻译：
靶向相关 HDAC 以支持遗传性视网膜疾病中视锥光感受器的存活：鉴定具有体外和体内功效的有效药理学工具
遗传性视网膜疾病，包括色素性视网膜炎，是一类遗传性疾病，其特征是逐渐的视锥细胞变性和视力丧失，且没有有效的药物治疗。实验方法旨在延缓疾病进展，支持视锥细胞的生存，这对人类视觉至关重要。组蛋白脱乙酰酶 (HDAC) 介导表观遗传和非表观遗传途径的激活，从而调节 RP 小鼠模型中的视锥细胞变性。我们开发了新的 HDAC 抑制剂 ( 5a – p )，以四氢-γ-咔啉支架为代表，其特点是具有高 HDAC6 抑制效力和平衡的理化特性，适合体内研究。与 ARPE-19 和 661W 细胞中的组蛋白 H3 相比，化合物5d （ repistat ，IC 50 HDAC6 = 6.32 nM）增加了乙酰化 α-微管蛋白的水平。 5d促进了atp6v0e1 –/–光感受器功能障碍斑马鱼模型的视力挽救。在 RP rd10小鼠模型中单次玻璃体内注射5d支持视锥细胞的形态和功能保存以及视网膜色素上皮阵列的维持。
更新日期：2024-07-04
中文翻译：
靶向相关 HDAC 以支持遗传性视网膜疾病中视锥光感受器的存活：鉴定具有体外和体内功效的有效药理学工具
遗传性视网膜疾病，包括色素性视网膜炎，是一类遗传性疾病，其特征是逐渐的视锥细胞变性和视力丧失，且没有有效的药物治疗。实验方法旨在延缓疾病进展，支持视锥细胞的生存，这对人类视觉至关重要。组蛋白脱乙酰酶 (HDAC) 介导表观遗传和非表观遗传途径的激活，从而调节 RP 小鼠模型中的视锥细胞变性。我们开发了新的 HDAC 抑制剂 ( 5a – p )，以四氢-γ-咔啉支架为代表，其特点是具有高 HDAC6 抑制效力和平衡的理化特性，适合体内研究。与 ARPE-19 和 661W 细胞中的组蛋白 H3 相比，化合物5d （ repistat ，IC 50 HDAC6 = 6.32 nM）增加了乙酰化 α-微管蛋白的水平。 5d促进了atp6v0e1 –/–光感受器功能障碍斑马鱼模型的视力挽救。在 RP rd10小鼠模型中单次玻璃体内注射5d支持视锥细胞的形态和功能保存以及视网膜色素上皮阵列的维持。
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