Researchers screen dual main protease-cathepsin L inhibitors against SARS-CoV-2

The main protease of SARS-CoV-2 (MPRO) is essential to viral replication, being highly conserved from SARS-CoV-1 through to SARS-CoV-2 and its variants. It has therefore been widely explored as a drug target throughout the course of the COVID-19 pandemic. Certain host proteases are also involved in priming the SARS-CoV-2 spike protein for viral packaging and assisting in cell entry, including transmembrane protease serine 2 (TMPRSS2), furin, and cathepsin L, and inhibitors to these proteins have shown some efficacy in preventing and fighting SARS-CoV-2 infection.

In a recent study released on the bioRxiv* preprint server, a selective dual inhibitor of MPRO and cathepsin L is described, producing synergistic results that suppress SARS-CoV-2 infection.

Investigating dual inhibitors

MPRO and cathepsin L are cysteine protease enzymes, with the former bearing an active site around the Cys145 residue that is the target of most MPRO inhibitors in development, which usually possess an aldehyde or α-ketoamide group that forms an irreversible covalent bond with this site. The group selected 11 peptidomimetic aldehydes and three diaryl esters that had previously reported inhibition potency towards MPRO, furin, TMPRSS2, or cathepsin L to be investigated, and host proteases cathepsin B and K were also exposed to the drugs to investigate the specificity of the interaction.

Most of the peptidomimetic aldehydes tested inhibited cathepsins B, K, and L very strongly in vitro, cathepsin L in particular. Cathepsin L and MPRO share structural similarities within their S1 pocket, with a glutamine residue being favored at the P1 position. At P2, MPRO favors leucine and other hydrophobic molecules, while cathepsin L P2 is specific to aliphatic residues, which are hydrophobic. The group suggests that these common structural and electrochemical similarities are the reason for the enhanced affinity observed amongst the peptidomimetic aldehydes, while the diaryl esters potently inhibited MPRO but had no inhibitory activity against any of the cathepsins. Diaryl esters could, therefore, make excellent highly specific MPRO inhibitors in future work.

Four of the peptidomimetic aldehyde drugs, in particular, were picked out as potent dual-inhibitors, inhibiting cathepsins B and K the least, though still somewhat, and also inhibiting cellular lysosomal activity as a result. The molecule termed MP18 in the paper exhibited the most cellular MPRO inhibition and had the highest selectivity towards capthepsin L over cathepsins B or K, being demonstrated to be a potent antiviral in vitro.

One major advantage of the dual target mechanism is the lowered chance of resistance occurring, though the group also indicate that the inclusion of a human protease as a drug target could increase the chances of adverse events occurring. Cathepsin L is the only cathepsin enzyme that has been demonstrated to be involved with assisting SARS-CoV-2 in cell entry, and disrupting those that are unrelated would induce significant negative effects. Furin and TMPRSS2 activity was unaffected by any of the drugs tested in this study.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Michael Greenwood

Written by

Michael Greenwood

Michael graduated from Manchester Metropolitan University with a B.Sc. in Chemistry in 2014, where he majored in organic, inorganic, physical and analytical chemistry. He is currently completing a Ph.D. on the design and production of gold nanoparticles able to act as multimodal anticancer agents, being both drug delivery platforms and radiation dose enhancers.


Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Greenwood, Michael. (2021, June 15). Researchers screen dual main protease-cathepsin L inhibitors against SARS-CoV-2. News-Medical. Retrieved on August 02, 2021 from

  • MLA

    Greenwood, Michael. "Researchers screen dual main protease-cathepsin L inhibitors against SARS-CoV-2". News-Medical. 02 August 2021. <>.

  • Chicago

    Greenwood, Michael. "Researchers screen dual main protease-cathepsin L inhibitors against SARS-CoV-2". News-Medical. (accessed August 02, 2021).

  • Harvard

    Greenwood, Michael. 2021. Researchers screen dual main protease-cathepsin L inhibitors against SARS-CoV-2. News-Medical, viewed 02 August 2021,


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
You might also like... ×
Scientists identify natural SARS-CoV-2 super immunity against 23 variants