Liu J, Shikhman A R, Lotz M K, Wong C H
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Chem Biol. 2001 Jul;8(7):701-11. doi: 10.1016/s1074-5521(01)00045-x.
Articular cartilage from patients with osteoarthritis is characterized by a decreased concentration and reduced size of glycosaminoglycans. Degeneration of the cartilage matrix is a multifactorial process, which is due in part to accelerated glycosaminoglycan catabolism. Recently, we have demonstrated that hexosaminidase represents the dominant glycosaminoglycan-degrading glycosidase released by chondrocytes into the extracellular compartment and is the dominant glycosidase in synovial fluid from patients with osteoarthritis. Inhibition of hexosaminidase activity may represent a novel approach to the prevention of cartilage matrix glycosaminoglycan degradation and a potentially new strategy to treat osteoarthritis.
We have synthesized and investigated a series of iminocyclitols designed as transition-state analog inhibitors of human hexosaminidase, and demonstrated that the five-membered iminocyclitol 4 expresses the strongest inhibitory activity with K(i)=24 nM. Inhibition of hexosaminidase activity in human cultured articular chondrocytes and human chondrosarcoma cells with iminocyclitol 4 resulted in accumulation of hyaluronic acid and sulfated glycosaminoglycans in the cell-associated fraction. Similarly, incubation of human cartilage tissue with iminocyclitol 4 resulted in an accumulation of glycosaminoglycans in the pericellular compartment.
Inhibition of hexosaminidase activity represents a new strategy for preventing or even reversing cartilage degradation in patients with osteoarthritis.
骨关节炎患者的关节软骨具有糖胺聚糖浓度降低和大小减小的特征。软骨基质的退化是一个多因素过程，部分原因是糖胺聚糖分解代谢加速。最近，我们已经证明己糖胺酶是软骨细胞释放到细胞外区室的主要糖胺聚糖降解糖苷酶，并且是骨关节炎患者滑液中的主要糖苷酶。抑制己糖胺酶活性可能代表一种预防软骨基质糖胺聚糖降解的新方法以及一种潜在的治疗骨关节炎的新策略。
我们合成并研究了一系列设计为人己糖胺酶过渡态类似物抑制剂的亚氨基环醇，并证明五元亚氨基环醇4表现出最强的抑制活性，K(i)=24 nM。用亚氨基环醇4抑制人培养的关节软骨细胞和人软骨肉瘤细胞中的己糖胺酶活性导致透明质酸和硫酸化糖胺聚糖在细胞相关部分积累。同样，用人软骨组织与亚氨基环醇4孵育导致糖胺聚糖在细胞周围隔室中积累。
抑制己糖胺酶活性代表了一种预防甚至逆转骨关节炎患者软骨降解的新策略。
