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Structure-based development of an osteoprotegerin-like glycopeptide that blocks RANKL/RANK interactions and reduces ovariectomy-induced bone loss in mice
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2018-01-10 , DOI: 10.1016/j.ejmech.2018.01.022
Chao Liu , Xiao Chen , Xin Zhi , Weizong Weng , Quan Li , Xiang Li , Yan Zou , Jiacan Su , Hong-Gang Hu

Osteoporosis is a metabolic bone disease characterized by low bone mass and micro-architectural deterioration of bone, for which the underlying mechanism is an imbalance between bone resorption and bone remodeling. The protein-protein interactions between receptor activator of nuclear factor-κB ligand (RANKL), RANK (its receptor), and osteoprotegerin (OPG), are known to mediate the development and activation of osteoclasts in bone remodeling, and are regarded as a pivotal therapeutic target for the treatment of osteoporosis. Herein, we disclose the successful development of a novel glycopeptide (OM-2), the structure of which is based on the key interacting sites of the reported RANKL and OPG crystal structure. OM-2 exhibited potent binding affinity with RANKL and resistance to degradation by protease enzymes. It also blocked RANKL/RANK interactions, and inhibited osteoclastogenesis in vitro. In vivo studies confirmed that OM-2 could effectively reduce bone loss and inhibit osteoclast activation in ovariectomized (OVX) mice at a dosage of 20.0 mg/kg/day. Accordingly, OM-2 is suggested as a therapeutic candidate for postmenopausal osteoporosis (PMOP) and osteoclastogenesis-related diseases like rheumatoid arthritis (RA). More importantly, its identification validates our structure-based strategy for the development of drugs that target the RANKL/RANK/OPG system.



中文翻译:

骨保护素样糖肽的基于结构的发育,该蛋白肽可阻断RANKL / RANK相互作用并减少卵巢切除术引起的小鼠骨质流失

骨质疏松症是一种代谢性骨病,其特征是骨量低和骨骼的微结构退化,其潜在机制是骨骼吸收与骨骼重塑之间的不平衡。众所周知,核因子-κB配体的受体激活剂(RANKL),RANK(其受体)和破骨保护素(OPG)之间的蛋白质相互作用可介导破骨细胞在骨重塑中的发展和激活,并被认为是关键的骨质疏松症的治疗目标。在这里,我们公开了新型糖肽(OM-2)的成功开发,其结构基于已报道的RANKL和OPG晶体结构的关键相互作用位点。OM-2与RANKL表现出强大的结合亲和力,并具有抵抗蛋白酶降解的能力。体外体内研究证实,以20.0 mg / kg /天的剂量,OM-2可以有效减少卵巢切除(OVX)小鼠的骨质流失并抑制破骨细胞活化。因此,OM-2被建议作为绝经后骨质疏松症(PMOP)和类风湿关节炎(RA)等与破骨细胞生成相关疾病的治疗候选药物。更重要的是,它的识别验证了我们针对RANKL / RANK / OPG系统开发药物的基于结构的策略。

更新日期:2018-01-10
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