Structure–activity relationship of marinostatin,a serine protease inhibitor isolated from a marine organism |
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| Authors: | Misako Taichi Tohimasa Yamazaki Kazuki Kawahara Daisuke Motooka Shota Nakamura Shusaku Harada Tadashi Teshima Tadayasu Ohkubo Yuji Kobayashi Yuji Nishiuchi |
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| Affiliation: | 1. SAITO Research Center, Peptide Institute, Inc., Ibaraki, Osaka 567‐0085, Japan;2. Graduate School of Science, Osaka University, Toyonaka, Osaka 560‐0043, Japan;3. Protein Research Unit, National Institute of Agrobiological Science, Tsukuba, Ibaraki 305‐8602, Japan;4. Graduate School of Pharmaceutical Science, Osaka University, Suita, Osaka 565‐0871, Japan;5. Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 567‐0871, Japan;6. Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569‐1094, Japan |
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| Abstract: | A 12‐residue MST isolated from a marine organism is a potent serine protease inhibitor that has a double cyclic structure composed of two ester linkages formed between the β‐hydroxyl and β‐carboxyl groups, Thr3‐Asp9 and Ser8‐Asp11. MST was synthesized by a regioselective esterification procedure employing two sets of orthogonally removable side‐chain protecting groups for the Asp and Ser/Thr residues. In the MST molecule, there were no significant changes observed in yield by changing the order of esterification. SAR study of MST revealed that the minimum required structure for expressing the inhibitory activity is the sequence (1–9) in a monocyclic structure where Pro7 located in the ring plays a crucial role in keeping the structural rigidity. By applying the structural motif of MST, we rationally designed protease inhibitory specificities that differ from those of the natural product. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. |
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| Keywords: | ester linkage MST NMR analysis peptide synthesis SAR study serine protease inhibitor solution structure |
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