Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients

Pharmacol Ther. 2020 Sep;213:107587. doi: 10.1016/j.pharmthera.2020.107587. Epub 2020 May 26.


The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2,118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.

Keywords: COVID-19; Camostat mesylate; Cathepsin L; Chloroquine; Nafamostat mesylate; Protease inhibitor cocktail; SARS-CoV-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Antigen-Presenting Cells / metabolism
  • Antimalarials / pharmacology
  • Antimalarials / therapeutic use
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use*
  • Betacoronavirus
  • COVID-19
  • Cathepsin L / antagonists & inhibitors*
  • Clinical Trials as Topic / statistics & numerical data
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / physiopathology*
  • Dose-Response Relationship, Drug
  • Drug Approval
  • Drug Therapy, Combination
  • Humans
  • Immunologic Factors / pharmacology
  • Immunologic Factors / therapeutic use
  • Medicine, Chinese Traditional / methods
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / physiopathology*
  • SARS-CoV-2
  • Serine Endopeptidases / metabolism
  • United States
  • United States Food and Drug Administration


  • Anti-Bacterial Agents
  • Antimalarials
  • Antiviral Agents
  • Immunologic Factors
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • Cathepsin L