by Maria Giulia Manzione
Proteases, also known as proteolytic enzymes, are molecular scissors that cut proteins. In humans, proteases are involved in several important processes. For example, during digestion proteases actively work to break down food-derived proteins into smaller fragments to provide nutrients. Another example is blood coagulation, in which the protease thrombin at a final step creates fibrin, which forms the meshwork of a blood clot.
Viruses, including the coronavirus responsible for the current pandemic (SARS-CoV-2), produce proteases needed for viral replication and survival. That is why viral proteases are attractive targets for the development of antiviral drugs. Thus, scientists have designed small chemical tools, known as activity-based probes, to detect, isolate, and characterize specific active proteases even in “noisy” environments, such as human cells. With these probes scientists can then more easily find drugs that target these proteases and thereby prevent viruses from replicating.
Researchers from the Laboratory of Chemical Biology at KU Leuven have recently developed a probe that specifically recognizes the main protease of SARS-CoV-2, called Mpro.
“You can think about probes as fishhooks. Once the active viral protease (the “fish”) bites down onto the fishhook it will be permanently attached to the protease. Then, if you attach a fluorophore (a molecule that emits light) to the fishhook you can easily detect the protease”
In an article by Merel van de Plassche et al., the authors designed multiple probes (containing a reactive group attached to a specific sequence of amino acids) that can be recognized by the viral protease (Mpro). Then, they screened the obtained probes against active Mpro and selected the most sensitive one. “We found that the selectivity of our probe against SARS-CoV-2 protease was very high over the human proteases” said Prof. Steven Verhelst. Moreover, this probe designed by Merel van de Plassche et al. is a flexible tool that can be used to recognize other viral proteases “by changing the recognition (peptide) element specific for other proteases”.
The probe can be further modified by adding a fluorophore to it. That helps researchers to visualise the protease, to learn more about the protease and its role in the multiplication of the virus. The probe can also be used as a tool to develop new drugs against the SARS-CoV-2 protease. “We would like to move forward and see if we can use the probes to visualize the proteases in human infected cells treated with anti-viral compounds. In this way we hope to verify in real-time if and which compounds effectively target the protease” said Prof. Steven Verhelst.
The interesting aspect of such probes is that they allow researchers to detect the activity of proteases. Having a tool to measure or detect the activity of a protease is important not only to understand the biological function of the protein but also to speed up the research of new potential drugs.
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