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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| Abstract |
Matriptase, initially isolated from human breast cancer cells in culture, is a member of the emerging class of type II transmembrane serine proteases. Matriptase blockade could potentially modulate tumorigenesis and metastasis in vivo. Sunflower trypsin inhibitor-1 (1, SFTI-1), isolated from sunflower seeds, exhibits very potent matriptase inhibitory activity. On the basis of these findings, we designed and synthesized 13 analogues of the naturally occurring peptide 1 with the intention to explore the structure-activity relationships of 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 demonstrates very potent binding affinity to matriptase. Compound 8 exhibits much better selectivity for inhibition of matriptase versus thrombin, whereas compound 2 becomes a more potent thrombin inhibitor, which can be potentially used as an anticoagulant for prophylaxis and therapy of thromboembolism.
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| Authors | Peng Li, Sheng Jiang, Sheau-Ling Lee, Cheng Yong Lin, Michael D Johnson, Robert B Dickson, Christopher J Michejda, Peter P Roller |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 24 Pg. 5976-83 (Nov 29 2007) ISSN: 0022-2623 [Print] United States |
| PMID | 17985858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural) |
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