Tanshinones that selectively block the collagenase activity of cathepsin K provide a novel class of ectosteric antiresorptive agents for bone
Tanshinones that selectively block the collagenase activity of cathepsin K provide a novel class of ectosteric antiresorptive agents for bone
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DOI：
10.1111/bph.14133
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发表时间：
2018-03-01
影响因子：
7.3
通讯作者：
Bromme, Dieter
中科院分区：
文献类型：
--
作者：
Panwar, Preety;Law, Simon;Bromme, Dieter
背景和目的：由于副作用，产生活性的定点定向组织蛋白酶K(CatK)抑制剂治疗骨质疏松症的尝试失败了。我们先前已经证明从丹参中分离出的一种外型丹参酮CatK抑制剂选择性地阻断CatK的胶原酶活性，而不影响活性部位，并在体内证明了其保骨活性。在这里，我们表征了其他丹参酮的抗吸收潜力，这可能为无副作用的CatK抑制剂提供支架。实验用酶法和细胞分析法测试了丹参酮对CatK的活性。通过扫描电子显微镜和机械强度测量，在酶分析中确定了其对三螺旋和纤维状胶原降解的抑制效力。用人破骨细胞实验来确定这些抑制剂对骨吸收、其可逆性和破骨细胞生成的影响。KEY结果12个化合物显示出高效的抗胶原酶活性，在不抑制非胶原底物的水解性的情况下，保护胶原免受破坏和机械不稳定性。6个化合物在破骨细胞骨吸收实验中具有很高的效率，其IC50值为
BACKGROUND AND PURPOSEAttempts to generate active site-directed cathepsin K (CatK) inhibitors for the treatment of osteoporosis have failed because of side effects. We have previously shown that an ectosteric tanshinone CatK inhibitor isolated from Salvia miltiorrhiza blocked, selectively, the collagenase activity of CatK, without affecting the active site and demonstrated its bone-preserving activity in vivo. Here, we have characterize the antiresorptive potential of other tanshinones, which may provide a scaffold for side effect-free CatK inhibitors.EXPERIMENTAL APPROACHThirty-one tanshinones were tested for their activity against CatK in enzymic and cell-based assays. The inhibitory potency against triple helical and fibrillar collagen degradation was determined in enzymic assays, by scanning electron microscopy and mechanical strength measurements. Human osteoclast assays were used to determine the effects of the inhibitors on bone resorption, its reversibility and osteoclastogenesis. Binding sites were characterized by molecular docking.KEY RESULTSTwelve compounds showed highly effective anti-collagenase activity and protected collagen against destruction and mechanical instability without inhibiting the hydrolysis of non-collagenous substrates. Six compounds were highly effective in osteoclast bone resorption assays with IC50 values of