A Synthetic Serine Protease Inhibitor, Nafamostat Mesilate, Is a Drug Potentially Applicable to the Treatment of Ebola Virus Disease.
Ebola virus disease (EVD) has been a great concern worldwide because of its high mortality. EVD usually manifests with fever, diarrhea and vomiting, as well as disseminated intravascular coagulation (DIC). To date, there is neither a licensed Ebola vaccine nor a promising therapeutic agent, although clinical trials are ongoing. For replication inside the cell, Ebola virus (EBOV) must undergo the proteolytic processing of its surface glycoprotein in the endosome by proteases including cathepsin B (CatB), followed by the fusion of the viral membrane and host endosome. Thus, the proteases have been considered as potential targets for drugs against EVD. However, no protease inhibitor has been presented as effective clinical drug against it. A synthetic serine protease inhibitor, nafamostat mesilate (NM), reduced the release of CatB from the rat pancreas. Furthermore, it has anticoagulant activities, such as inhibition of the factor VIIa complex, and has been used for treating DIC in Japan. Thus, NM could be considered as a drug candidate for the treatment of DIC induced by EBOV infection, as well as for the possible CatB-related antiviral action. Moreover, the drug has a history of large-scale production and clinical use, and the issues of safety and logistics might have been cleared. We advocate in vitro and in vivo experiments using active EBOV to examine the activities of NM against the infection and the DIC induced by the infection. In addition, we suggest trials for comparison among anti-DIC drugs including the NM in EVD patients, in parallel with the experiments.
Virus Research Center, Clinical Research Division, Sendai Medical Center.
Hidekazu
H
Nishimura
Mutsuo
M
Yamaya
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001550:Benzamidines; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy / Q000209:etiology; D029043:Ebolavirus / Q000187:drug effects* / Q000201:enzymology; D015942:Factor VIIa / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000627:therapeutic use*; D019142:Hemorrhagic Fever, Ebola / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D006947:Hyperkalemia / Q000209:etiology / Q000628:therapy; D007010:Hyponatremia / Q000209:etiology / Q000628:therapy; D051381:Rats; D057057:Serine Proteases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D001550:Benzamidines; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases; D015942:Factor VIIa; C032855:nafamostat