Related Experiment Video
Updated: Sep 7, 2026
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Identification of Z-Tyr-Ala-CHN2, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against
Jordi Doijen1, Koen Temmerman1, Christel Van den Eynde1
1Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Abstract:
The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.
Insights
A novel small molecule, Z-Tyr-Ala-CHN2, shows potent antiviral activity against SARS-CoV-2 and other coronaviruses. This compound inhibits cathepsin L, offering a potential new avenue for developing COVID-19 therapeutics.
Area of Science:
- Virology
- Drug Discovery
- Biochemistry
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, necessitates the development of effective antiviral drugs.
- Vaccination is a key control measure, but potent antivirals are still crucial for managing severe disease.
Purpose of the Study:
- To discover and characterize novel small molecules with antiviral activity against SARS-CoV-2.
- To investigate the mechanism of action and cellular activity of identified compounds.
Main Methods:
- Conducted a cell-based antiviral screen to identify potential drug candidates.
- Performed time-of-addition studies to determine the stage of viral infection targeted.
- Assessed antiviral activity across different cell lines, including those expressing ACE2 and TMPRSS2.
Main Results:
- Identified Z-Tyr-Ala-CHN2, a small molecule with sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and HCoV-229E.
- Demonstrated that Z-Tyr-Ala-CHN2 inhibits cathepsin L, acting early in the viral infection cycle.
- Observed cell-specific antiviral activity, effective in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 or primary human nasal epithelial cells.
Conclusions:
- Z-Tyr-Ala-CHN2 is a potent inhibitor of cathepsin L with broad-spectrum coronavirus activity.
- The cell-specific activity highlights the importance of viral entry pathways (e.g., TMPRSS2) in determining drug efficacy.
- Z-Tyr-Ala-CHN2 serves as a valuable tool compound for further research into coronavirus entry and replication mechanisms.
