Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry
详细信息 查看全文
- 作者：Janina Schmitz ; Tianwei Li ; Ulrike Bartz ; Michael Gütschow
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：7
- 期：3
- 页码：211-216
- 全文大小：351K
- 年卷期：Michael Gütschow studied Biochemistry and received his Ph.D. in Pharmaceutical Chemistry from the University of Leipzig, Germany. After postdoctoral training at the Georgia Institute of Technology, School of Chemistry and Biochemistry, he returned to the University of Leipzig and was appointed as a professor for Pharmaceutical Chemistry at the University of Bonn in 2001. His research interests include (i) synthesis of bioactive heterocycles, (ii) peptides and peptidomimetic drugs, (iii) development of inhibitors and activity-based probes of proteases and esterases, and (iv) biochemistry of enzyme−drug interactions. He has published approximately 190 publications on these scientific topics.
- ISSN：1948-5875
文摘
An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-connected molecules was applied. Inhibitor 17 exhibited Ki values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models.