Mechanism of the action of SMTP-7, a novel small-molecule modulator of plasminogen activation.
SMTP-7 is a small molecule that promotes the proteolytic activation of plasminogen by relaxing its conformation. SMTP-7 has excellent therapeutic activities against thrombotic stroke in several rodent models. The objective of this study was to elucidate detailed mechanism of the action of SMTP-7 in vitro. We report here that the action of SMTP-7 requires a cofactor with a long-chain alkyl or alkenyl group, and that the fifth kringle domain (kringle 5) of plasminogen is involved in the SMTP-7 action. In this study, we found that the SMTP-7 action to enhance plasminogen activation depended on the presence of a certain type of surfactant, and we screened biologically relevant molecules for their cofactor activity for the SMTP action. As a result, phospholipids, sphingolipids, and oleic acid were found to be active in assisting the SMTP-7 action. On the contrary, stearic acid and bile acids were inactive. Thus, a certain structural element, not only the surface-activating potential, is required for a compound to act as a cofactor for the SMTP-7 action. The plasminogen molecule consists of a PAN domain, five kringle domains, and a serine protease domain. The cofactor-dependent effects of SMTP-7 was observed with plasminogen species including kringle 5 such as intact plasminogen (Glu-plasminogen), des-PAN plasminogen (Lys-plasminogen), and des-[PAN - (kringles 1-4)] plasminogen (mini-plasminogen). However, SMTP-7 effect was not observed with the smallest plasminogen species des-[PAN - (kringles 1-4) and a half of kringle 5)] plasminogen (micro-plasminogen). Thus, kringle 5 is crucial for the action of SMTP-7.
Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
Keiji
K
Koyanagi
Ritsuko
R
Narasaki
Shingo
S
Yamamichi
Eriko
E
Suzuki
Keiji
K
Hasumi
D001578:Benzopyrans / Q000494:pharmacology*; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D018082:Kringles / Q000187:drug effects; D010713:Phosphatidylcholines / Q000494:pharmacology; D010718:Phosphatidylserines / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism*; D011136:Polysorbates / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D001578:Benzopyrans; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D011136:Polysorbates; D011760:Pyrrolidinones; C409191:SMTP 7; D013501:Surface-Active Agents; D005337:Fibrin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator