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Thromb Haemost 1998; 79(03): 591-596
DOI: 10.1055/s-0037-1614951
Review Articles
Schattauer GmbH

Enhancement of Fibrinolysis by Plactins: Structure-activity Relationship and Effects in Human U937 Cells and in Mice

Toshiki Inoue
1   From the Department of Applied Biological Science, Tokyo Noko University, Fuchu, Tokyo, Japan
,
Keiji Hasumi
1   From the Department of Applied Biological Science, Tokyo Noko University, Fuchu, Tokyo, Japan
,
Maki Sugimoto
1   From the Department of Applied Biological Science, Tokyo Noko University, Fuchu, Tokyo, Japan
,
Akira Endo
1   From the Department of Applied Biological Science, Tokyo Noko University, Fuchu, Tokyo, Japan
› Author Affiliations
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Publication History

Received 13 June 1997

Accepted after revision 24 November 1997

Publication Date:
07 December 2017 (online)

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Summary

Plactin D, a cyclic pentapeptide [ cyclo (-D-Val-L-Leu-D-Leu-LPhe-D-Arg-)] produced by a fungal strain, enhances fibrinolytic activity (6). The present study deals with the structure-activity relationship of plactins and their effects in U937 cells and mice. The results obtained from 50 plactin D analogues with a single amino acid substitution demonstrated that the following substitutions were detrimental: the enantiomer for each of the five residues; a polar, an acidic or a basic residue for D-Val, L-Leu, D-Leu or L-Phe; a polar, a hydrophobic or an acidic residue for D-Arg. On the other hand, a compound with L-Leu or L-Val in place of L-Phe was seven times as active as plactin D. These results suggest an essential role of a sterically restricted arrangement of four hydrophobic residues and the adjacent basic residue. The enhancement of fibrinolysis was dependent on plasma, ranging from 2- to 3-fold when U937 cells were incubated with 15-30 μM plactin D in the presence of 6-50% plasma, while no elevation was observed when cells were incubated in the absence of plasma. Plasminogen alone could not substitute for plasma. The plactin D effect was totally abolished by anti-urokinase IgG but not by anti-tissue plasminogen activator IgG. Plactin D caused a plasma-dependent, transient increase in the cellular urokinase activity. This urokinase activation may have accounted for the increased fibrinolytic activity of plactin D-treated U937 cells. Homogenates of the lung obtained from mice 0.5 to 2 h after intravenous plactin D (5 mg/kg) showed 2- to 3-fold increased levels of fibrinolytic activity, while activities of the brain, heart, liver, spleen, kidney and aorta were not significantly affected. In conclusion, plactin D enhances fibrinolysis both in cultured mammalian cells and in experimental animals.

 

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