Virus World

Although infection by SARS-CoV-2, the causative agent of COVID-19, is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked MERS-CoV S protein-initiated cell fusion by targeting TMPRSS2, and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells.

Here we established a quantitative fusion assay dependent on SARS-CoV-2 S protein, ACE2 and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an EC50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. These findings, together with accumulated clinical data regarding its safety, make nafamostat a likely candidate drug to treat COVID19.

Researchers led by Duke-NUS Medical School have discovered that tryptase, an enzyme in human cells that acts like scissors to cut up nearby proteins, is responsible for blood vessel leakage in severe dengue hemorrhagic fever. The finding suggests a possible new treatment strategy using the tryptase inhibitor, nafamostat mesylate, for severe dengue disease—a potentially fatal condition for which no targeted treatment is currently available.

The dengue virus infects about 390 million people globally each year, causing substantial morbidity and mortality. While most patients experience dengue fever or a mild form of the disease, a small percentage develops dengue hemorrhagic fever (DHF), the more severe occurrence of dengue wherein blood 'leaks' from ruptured blood vessels. This can lead to dengue shock syndrome (DSS) – the final stage of DHF—where the circulatory system fails, sending the body into bleeding and shock, which is fatal without prompt treatment. 

How dengue patients go on to develop these severe conditions had not been clearly understood and, as a result, no targeted treatments have been developed to prevent hemorrhaging or reverse shock in infected patients. "We discovered that, in severe cases, a particular enzyme called tryptase cuts the proteins that act as seals between blood vessel cells, resulting in blood vessel leakage and shock during dengue infection," said Assistant Professor Ashley St. John, from Duke-NUS' Emerging Infectious Diseases Programme, corresponding author of the study.

Based on this finding, the team wanted to know if a drug specific to inhibiting tryptase could be used to treat the hemorrhaging. Nafamostat mesylate, a clinically-approved tryptase inhibitor with a good safety profile, was tested using preclinical models. They found that administration of this drug, which is already used for the treatment of certain bleeding complications in some countries, prevented vascular leakage in the dengue model. Even delayed treatment with the drug was significantly effective in reducing dengue vascular leakage in a preclinical model of severe disease. The team also observed tryptase levels were very high in the blood of severe dengue patients who experienced DHF/DSS, but low in patients who easily recovered, affirming the link between high levels of the enzyme and severe dengue disease.

The findings were first published on July 2, 2019 in the Journal of Clinical Investigation:

https://doi.org/10.1172/JCI128426