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.

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。