Yang Yi, Geng Chenchen, Shen Huaxing, Chao Jingru, Wang Zhe, Cong Wei, Li Xiang, Ye Guangming, Jiang Yunyun
School of Pharmacy, Anhui Medical University, HeFei 230032, China.
School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
ACS Med Chem Lett. 2024 Jul 10;15(8):1242-1249. doi: 10.1021/acsmedchemlett.4c00127. eCollection 2024 Aug 8.
Osteoporosis, a global bone disease, results in decreased bone density, mass, and microarchitecture deterioration, increasing fracture risk. In previous research, FRATtide, a peptide derived from a glycogen synthase kinase-3 binding protein, effectively hindered osteoclast differentiation to yield therapeutically potent derivatives via single and double stapling. However, FRATtide's structure-activity relationship remains unclear. This study synthesized 25 FRATtide-derived peptides through systematic alanine scanning and evaluated their activities. Substitutions in Pro, Leu, Leu, Val, Leu, Ser Asn, Leu, Ile, Glu, Arg, Ser, and Arg showed reduced activity, while FRT13 and FRT20 with Gly and Arg substitutions, respectively, displayed enhanced activities. F-actin binding and bone resorption assays on FRT13 and FRT20 showed better inhibition of osteoclast differentiation and bone resorption compared with FRATtide. This study elucidated FRATtide's structure-activity relationship, thereby facilitating future structural optimization for osteoporosis treatment.
骨质疏松症是一种全球性的骨骼疾病，会导致骨密度降低、骨量减少以及微结构恶化，增加骨折风险。在先前的研究中，FRATtide是一种源自糖原合酶激酶-3结合蛋白的肽，通过单链和双链订书钉作用有效地阻碍破骨细胞分化，从而产生具有治疗潜力的衍生物。然而，FRATtide的构效关系仍不清楚。本研究通过系统的丙氨酸扫描合成了25种FRATtide衍生肽，并评估了它们的活性。脯氨酸、亮氨酸、亮氨酸、缬氨酸、亮氨酸、丝氨酸、天冬酰胺、亮氨酸、异亮氨酸、谷氨酸、精氨酸、丝氨酸和精氨酸的取代显示活性降低，而分别用甘氨酸和精氨酸取代的FRT13和FRT20显示活性增强。对FRT13和FRT20进行的F-肌动蛋白结合和骨吸收试验表明，与FRATtide相比，它们对破骨细胞分化和骨吸收的抑制作用更好。本研究阐明了FRATtide的构效关系，从而为未来骨质疏松症治疗的结构优化提供了便利。
