3CL Protease Inhibitors

3CL Protease Inhibitors: The Potential Key to Combating the SARS-CoV-2 Virus Life Cycle

The stages in the COVID virus life cycle include binding, entry, breakdown of proteins into smaller polypeptides or amino acids, and RNA replication.

COVID-19, like any other virus, is a single strand of RNA (or DNA) wrapped in a protein envelope. The RNA contains the genetic instructions the virus needs to make copies of itself. Viruses spread with a simple two-step process:

I. Break into a healthy cell

II. Hijack the cell’s own mechanisms to make copies of itself

Studies have shown, however, that by using protease inhibitors, we can stop the virus’ ability to replicate itself, halting the spread in it tracks. To understand how this is done, let’s take a closer look at the COVID virus lifecycle:


The coronavirus 3CL hydrolase enzyme, aka main protease, with an inhibitor bound in the active site.


First, the virus must get inside the cell. Every virus does this slightly differently, but coronaviruses (such as SARS-CoV-2) use their signature “spikes” to fuse themselves to a cell’s outer wall and then squeeze their way inside.



Once inside, the virus RNA converts into a polypeptide. This long protein is like a bus for the team of enzymes whose job it is to make more of the virus.


Before these enzymes can start working, they need to be separated from each other. The protease enzyme acts like a pair of scissors, cutting the polypeptide up into the different enzymes that then become functional.



When the protease enzyme comes in contact with a protease inhibitor, it is prevented from functioning. Protease inhibitor drugs are designed to tightly bind to the protease enzyme, blocking its ability to cleave. This shuts down the entire virus-making apparatus, leaving it unable to make a single virus.

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