Cathepsin Inhibitors a Possible Therapeutic Avenue to Prevent SARS-Cov-2 Infections

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Drugs that inhibit certain proteases -cathepsin inhibitors – could theoretically be helpful in preventing coronavirus infections in general.

How SARS-Cov-2 Enters Cells. © PLOS Pathogens

SARS-Cov-2 is not the first virus in its lineage. There are many other coronaviruses, most of which are endemic and benign, but some of which are more dangerous. The current pandemic is the largest we have seen in recent medical history. Every region of the world has been affected. Vaccines should hopefully get us out of this crisis soon. However, further research into treatments that could prevent coronavirus infection, in general, is essential if we are to be prepared against the coming viral threats from coronaviruses.

Scientists in Slovenia have been studying the potential value of cathepsin inhibitors – a family of enzymatic proteins used to break peptide bonds – and specifically, cathepsins that act at the level of cysteine – an amino acid – on peptide chains. In fact, SARS-CoV and SARS-Cov-2, two dangerous coronaviruses, use these enzymes to promote their replication in our cells. Researchers from the Department of Pharmaceutical Biology at the University of Ljubljana published their analysis on this in the journal PLOS Pathogens.

Preventing coronaviruses from replicating

Coronaviruses have two main strategies by which they enter our cells:

Endocytosis, in which the spike protein binds to angiotensin-2 receptors (ACE2) and transports the virus to a vesicle (the transport system of our cells).
membrane fusion, in which the same protein binds to the enzyme, Transmembrane Serine Protease 2 (TMPRSS2), and releases RNA directly into the cell.

Attempts are being made to intervene, at the level of the ACE2 receptors, to prevent the virus from entering our cells. Other experiments are working to develop drugs that could intervene later before the virus releases its genetic material into the cell. In Fact, the spike protein uses one of our enzymes, L-cathepsin, to activate itself so that the virus’ RNA can replicate in our cells. Therefore, it would make a lot of sense to inhibit this very enzyme. However, without clinical trials, we cannot know if it will work. In fact, Remdesivir, a drug made by the pharmaceutical company Gilead, works by inhibiting the action of the enzymes needed to replicate viral RNA – the polymerases.

More therapeutic approaches are needed

Since the SARS-Cov pandemic in 2002, many pathways have been explored against coronaviruses. Despite tremendous research efforts over the past few decades and especially this year in the fight against SARS-Cov-2, no treatment appears to be effective for prophylaxis. However, there is hope that by understanding more precisely how coronaviruses enter our cells, and by advancing our therapeutic methods, innovative treatments will be available for possible future epidemics. Basic research technology has advanced, as evidenced by the upcoming development of vaccines against SARS-CoV-2. Let us hope that this will continue to be the case.