Interpreting the behavior of concentration-response curves of hyaluronidase inhibitors under DMSO-perturbed assay conditions

详细信息    查看全文

• 作者：Keisuke Tomohara ; ^{tomohara@med.u-toyama.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Tomohiro Ito ; Saika Onikata ; Kota Furusawa ; Atsushi Kato ; Isao Adachi ; ^{adachi@med.u-toyama.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Hyaluronidase inhibitor ; Non-specific binding ; Concentration&ndash ; response curve ; DMSO ; Perturbation
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：26
• 期：13
• 页码：3153-3157
• 全文大小：813 K

文摘

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.