Interpreting the behavior of concentration-response curves of hyaluronidase inhibitors under DMSO-perturbed assay conditions
Interpreting the behavior of concentration-response curves of hyaluronidase inhibitors under DMSO-perturbed assay conditions
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解释 DMSO 扰动测定条件下透明质酸酶抑制剂浓度-反应曲线的行为
DOI：
10.1016/j.bmcl.2016.04.082
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发表时间：
2016
影响因子：
2.7
通讯作者：
Isao Adachi
中科院分区：
文献类型：
--
作者：
Keisuke Tomohara;Tomohiro Ito;Saika Onikata;Kota Furusawa;Atsushi Kato;Isao Adachi
透明质酸降解酶(透明质酸酶)与肿瘤的生长和炎症有关，因此，透明质酸酶抑制剂作为潜在的治疗药物最近受到了关注。以往的研究已经成功地发现了广泛的抑制剂，但遗憾的是，它们大多与原始配体透明质酸不同，其作用机制尚不清楚。目前的研究通过解释在几种体外测试条件下的浓度-反应曲线的行为，从机制上表征了这些结构无关的抑制剂。洗涤剂的添加条件明确确定了基于聚集的抑制剂。随后，DMSO扰动的条件，尽管是初步的，强调了可能与酶非特异性结合的抑制剂。这里，后一种描述的一个有趣的含义是，DMSO扰动的条件将产生非生产性但未变性的酶，该酶是有效物种的集合，以捕获非特定结合分子，从而将减弱它们的抑制活性。
Hyaluronan-degrading enzyme (hyaluronidase) is involved in tumor growth and inflammation, and as such, hyaluronidase inhibitors have received recent attention as potential therapeutics. The previous studies have successfully discovered a wide range of inhibitors, but unfortunately most of them are dissimilar to original ligand hyaluronan and the mode of action is poorly understood. The present study mechanistically characterized these structurally unrelated inhibitors by interpreting the behavior of concentration–response curves under several in vitro assay conditions. Detergent-addition conditions definitely identified aggregation-based inhibitors. Subsequently, DMSO-perturbed conditions, though preliminary, highlighted the inhibitors that might bind to enzyme non-specifically. Here, an intriguing implication of the latter description is that DMSO-perturbed conditions would generate non-productive but not-denatured enzyme that is an assembly of effective species to capture non-specific binding molecules, and thereby would attenuate their inhibitory activities.