Nafamostat Explained

Nafamostat mesylate (INN), a synthetic serine protease inhibitor, is a short-acting anticoagulant,^[1] and it is also used for the treatment of pancreatitis. It also has some potential antiviral and anti-cancer properties.^[2] Nafamostat is a fast-acting proteolytic inhibitor and used during hemodialysis to prevent the proteolysis of fibrinogen into fibrin.^[3] The mechanism of action of nafamostat is as a slow tight-binding substrate, trapping the target protein in the acyl-enzyme intermediate form, resulting in apparent observed inhibition.^{[4] [5]}

It inhibits a large number of Lys/Arg specific serine proteinases, and is also a tryptase inhibitor, which is implicated in leaking blood vessels which is symptomatic of dengue hemorrhagic fever and of end-stage dengue shock syndrome.^[6] It is available in a generic form already used for the treatment of certain bleeding complications in some countries, there are risks of severe complications such as: agranulocytosis, hyperkalemia, and anaphylaxis which must be weighed in non-emergency care.^[7] In some countries, it used as a treatment for pancreatitis and pancreatic cancer.

This drug has been identified as a potential therapy for COVID-19,^[8] with clinical trials in Japan possibly set to begin in March 2020.^[9] With evidence that nafamostat is a potent anti-viral inhibitor in lung cells, a second round of clinical trials in Korea has begun with 10 hospitals participating.^[10] Multiple Phase 2/3 and Phase 3 clinical trials for COVID-19 in different countries are ongoing.

Notes and References

1. Al-Horani RA, Desai UR . Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders . Medicinal Research Reviews . 34 . 6 . 1168–1216 . November 2014 . 24659483 . 8788159 . 10.1002/med.21315 . 22631056 .
2. Chen X, Xu Z, Zeng S, Wang X, Liu W, Qian L, Wei J, Yang X, Shen Q, Gong Z, Yan Y . 6 . The Molecular Aspect of Antitumor Effects of Protease Inhibitor Nafamostat Mesylate and Its Role in Potential Clinical Applications . Frontiers in Oncology . 9 . 852 . 2019 . 31552177 . 6733886 . 10.3389/fonc.2019.00852 . free .
3. Sadahiro T, Yuzawa H, Kimura T, Oguchi M, Morito T, Mizushima S, Hirose Y . Current Practices in Acute Blood Purification Therapy in Japan and Topics for Further Study . Contributions to Nephrology . 196 . 209–214 . 2018 . 30041229 . 10.1159/000485724 . 978-3-318-06297-7 .
4. Ramjee MK, Henderson IM, McLoughlin SB, Padova A . The kinetic and structural characterization of the reaction of nafamostat with bovine pancreatic trypsin . Thrombosis Research . 98 . 6 . 559–569 . June 2000 . 10899355 . 10.1016/s0049-3848(00)00206-1 .
5. Ramjee MK, Patel S . Continuous-flow injection microfluidic thrombin assays: The effect of binding kinetics on observed enzyme inhibition . Analytical Biochemistry . 528 . 38–46 . July 2017 . 28456636 . 10.1016/j.ab.2017.04.016 .
6. Rathore AP, Mantri CK, Aman SA, Syenina A, Ooi J, Jagaraj CJ, Goh CC, Tissera H, Wilder-Smith A, Ng LG, Gubler DJ, St John AL . 6 . Dengue virus-elicited tryptase induces endothelial permeability and shock . The Journal of Clinical Investigation . 129 . 10 . 4180–4193 . July 2019 . 31265436 . 6763290 . 10.1172/JCI128426 .
7. Web site: PubChem . Nafamostat. 17 June 2020 . U.S. National Library of Medicine . en.
8. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G . 6 . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro . Cell Research . 30 . 3 . 269–271 . March 2020 . 32020029 . 7054408 . 10.1038/s41422-020-0282-0 .
9. News: Japanese researchers to test blood thinner for coronavirus treatment. 19 March 2020 . The Japan Times Online. 24 March 2020 . en-US. 0447-5763.
10. Web site: Korean researchers find drug that is more effective in treating COVID-19 than remdesivir . 15 May 2020 . Pharmafile. 2020-06-17 . en-GB.