title: Design and synthesis of novel and potent inhibitors of the type II transmembrane serine protease, matriptase, based upon the sunflower trypsin inhibitor-1.
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.
authors.affiliation: Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Sheng
authors.initials: S
authors.lastname: Jiang
authors.forename: Sheau-Ling
authors.initials: SL
authors.lastname: Lee
authors.forename: Cheng Yong
authors.initials: CY
authors.lastname: Lin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Robert B
authors.initials: RB
authors.lastname: Dickson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Michejda
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C448501:SFTI-1 peptide, sunflower; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485595:matriptase