Design and Synthesis of Novel and Potent Inhibitors of the Type II Transmembrane Serine Protease, Matriptase, Based upon the Sunflower Trypsin Inhibitor-1

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• 作者：Peng Li ; Sheng Jiang ; Sheau-Ling Lee ; Cheng Yong Lin ; Michael D. Johnson ; Robert B. Dickson ; Christopher J. Michejda ; Peter P. Roller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：5976 - 5983
• 全文大小：414K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

Matriptase, initially isolated from human breast cancer cells in culture, is a member of the emerging classof type II transmembrane serine proteases. Matriptase blockade could potentially modulate tumorigenesisand metastasis in vivo. Sunflower trypsin inhibitor-1 (1, SFTI-1), isolated from sunflower seeds, exhibitsvery potent matriptase inhibitory activity. On the basis of these findings, we designed and synthesized 13analogues of the naturally occurring peptide 1 with the intention to explore the structure-activity relationshipsof this type of bicyclic peptides and to improve inhibitory selectivity and metabolic stability of the disulfide-bridge-containing peptide 1. We discovered that the methylenedithioether-bridged compound 14 demonstratesvery potent binding affinity to matriptase. Compound 8 exhibits much better selectivity for inhibition ofmatriptase versus thrombin, whereas compound 2 becomes a more potent thrombin inhibitor, which can bepotentially used as an anticoagulant for prophylaxis and therapy of thromboembolism.