Garibaldi Nadia, Besio Roberta, Pirota Valentina, Albini Benedetta, Colombo Giorgio, Galinetto Pietro, Doria Filippo, Carriero Alessandra, Forlino Antonella
Department of Biomedical Engineering, The City College of New York, New York, USA; Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
Life Sci. 2025 Jan 15;361:123320. doi: 10.1016/j.lfs.2024.123320. Epub 2024 Dec 18.
Osteogenesis imperfecta (OI) is a collagen I-related heritable family of skeletal diseases associated to extreme bone fragility and deformity. Its classical forms are caused by dominant mutations in COL1A1 and COL1A2, which encode for the protein α chains, and are characterized by impairment in collagen I structure, folding, and secretion. Mutant collagen I assembles in an altered extracellular matrix affecting mineralization and bone properties and partially accumulating inside the cells, leading to impaired trafficking and cellular stress. Recently, the chemical chaperone 4-phenylbutyrate (4-PBA) has been proposed as an innovative drug for OI based on its ability to restore intracellular homeostasis, stimulate secretion, and ameliorate collagen-producing cell functions, positively affecting bone properties. However, the limited half-life of the molecule represents a serious hurdle for its use.
To efficiently target cellular stress as OI treatment, two new compounds were designed by molecular modelling based on the 4-PBA structure to increase its stability and its ability to implement protein secretion. The short butyryl fatty acid chain of 4-PBA was substituted with a nitro functional group or with a glycine, respectively. The latter, N-benzyl glycine (N-BG), showed the best docking score, less toxicity, and higher stability than 4-PBA.
N-BG improved extracellular matrix quality and mineral content together with ameliorating OI cells' homeostasis by increasing ER-associated degradation pathway, reducing apoptosis, and stimulating protein secretion, thus facilitating intracellular clearance from accumulated misfolded proteins.
In conclusion, N-BG represents a novel potential available compound to target altered homeostasis in OI with the aim to ameliorate the disease phenotype.
成骨不全症（OI）是一种与I型胶原蛋白相关的遗传性骨骼疾病家族，与极端的骨脆性和畸形有关。其经典形式由编码蛋白质α链的COL1A1和COL1A2中的显性突变引起，其特征是I型胶原蛋白的结构、折叠和分泌受损。突变的I型胶原蛋白在改变的细胞外基质中组装，影响矿化和骨骼特性，并部分在细胞内积累，导致运输受损和细胞应激。最近，化学伴侣4-苯基丁酸（4-PBA）因其恢复细胞内稳态、刺激分泌和改善胶原蛋白生成细胞功能的能力，已被提议作为一种治疗OI的创新药物，对骨骼特性产生积极影响。然而，该分子有限的半衰期对其使用构成了严重障碍。
为了有效地将细胞应激作为OI的治疗靶点，基于4-PBA的结构通过分子建模设计了两种新化合物，以提高其稳定性和实现蛋白质分泌的能力。4-PBA的短丁酰脂肪酸链分别被硝基官能团或甘氨酸取代。后者，N-苄基甘氨酸（N-BG），显示出最佳的对接分数、更低的毒性和比4-PBA更高的稳定性。
N-BG改善了细胞外基质质量和矿物质含量，同时通过增加内质网相关降解途径、减少细胞凋亡和刺激蛋白质分泌来改善OI细胞的稳态，从而促进细胞内积累的错误折叠蛋白质的清除。
总之，N-BG代表了一种新型的潜在可用化合物，旨在改善OI疾病表型，靶向改变OI中的稳态。
