Skip to main content

Preventing the clinical manifestations and disease progression of coronavirus disease using clinically proven protease inhibitors

To the Editor:

Among the patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), older adults and those predisposed to cardiovascular or respiratory diseases are particularly vulnerable to severe complications, including acute respiratory distress syndrome (ARDS), multiple organ failure, and disseminated intravascular coagulation (DIC), all of which need critical care [1]. The production and application of effective and safe vaccines and/or drugs worldwide will require a substantial amount of time and cost. Thus, medically preventing the coronavirus disease (COVID-19) using the existing safe and mass-produced medicines is the need of the hour, especially to protect vulnerable populations.

Doi et al. reported that a combination treatment of favipiravir and nafamostat mesylate, a protease inhibitor, may be effective for critically ill patients with COVID-19, possibly via blockade of virus entry and replication as well as inhibition of hypercoagulopathy [2].

Not only to treat but also to decrease the number of critically ill patients with COVID-19, preventing the disease progression and clinical manifestation of COVID-19 is essential. Here, we additionally propose the prophylactic use of clinically proven protease inhibitors based on the following clinical and experimental evidence.

First, protease inhibitors, such as camostat mesylate and nafamostat mesylate, have long been used in the Japanese clinical practice with safe clinical outcomes. Second, these drugs suppress the entry of SARS-CoV-2 into cells via the angiotensin-converting enzyme 2 and transmembrane protease serine 2 [2, 3]. Third, nafamostat mesylate, an anticoagulant, has been widely used for extracorporeal circulation and in patients with DIC in Japan. Furthermore, thromboembolic events among hospitalized patients with COVID-19 have seen an increase, and anticoagulants could improve in-hospital mortality and survival [4]. Thus, protease inhibitors could also prevent an unfavorable prognosis of COVID-19, especially in cases with associated coagulopathies.

Finally, we demonstrated that the urinary trypsin inhibitor (UTI), another protease inhibitor, protects against systemic inflammation, ARDS, multiple organ failure, and DIC [5]. UTI prevents the accelerated expression of systemic inflammatory cytokines, which can contribute to the amelioration of the cytokine storm, a critical factor for the unfavorable prognosis of COVID-19.

Taken together, these clinically proven protease inhibitors can serve as promising prophylactics to prevent the manifestation and progression of COVID-19, by blocking the entry of SARS-CoV-2 and inhibiting subsequent inflammation, coagulopathies, and multiple organ failure in vulnerable populations, especially those who interact with patients with COVID-19, until vaccines and/or drugs suitable for the prevention and/or treatment of the disease are readily available worldwide.

Availability of data and materials

Not applicable.



Severe acute respiratory syndrome coronavirus 2


Coronavirus disease


Acute respiratory distress syndrome


Disseminated intravascular coagulation


Urinary trypsin inhibitor


  1. 1.

    Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet. 2020;395:1014–5.

    CAS  Article  Google Scholar 

  2. 2.

    Doi K, Ikeda M, Hayase N, Moriya K, Morimura N. Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series. Crit Care. 2020;24:392.

    Article  Google Scholar 

  3. 3.

    Yamamoto M, Kiso M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Imai M, Takeda M, et al. The anticoagulant nafamostat potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and viral infection in vitro in a cell-type-dependent manner. Viruses. 2020;12:629.

  4. 4.

    Paranjpe I, Fuster V, Lala A, Russak AJ, Glicksberg BS, Levin MA, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76:122–4.

    CAS  Article  Google Scholar 

  5. 5.

    Inoue KI, Takano H. Urinary trypsin inhibitor as a therapeutic option for endotoxin-related inflammatory disorders. Expert Opin Investig Drugs. 2010;19:513–20.

    CAS  Article  Google Scholar 

Download references





Author information




T.S. and H.T. designed the paper. All authors participated in drafting and reviewing. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Hirohisa Takano.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare to have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sagawa, T., Inoue, K. & Takano, H. Preventing the clinical manifestations and disease progression of coronavirus disease using clinically proven protease inhibitors. Crit Care 24, 511 (2020).

Download citation