3CL Protease Inhibitors

(aka 3CLpro / Main Protease / Mpro / NSP5)

Key to Combating the Virus Life Cycle

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

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

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 SARS-CoV-2 virus lifecycle: 


First, the virus must get inside the cell. Every virus does this slightly differently, but Coronaviruses use their signature “spikes” to fuse themselves to a cell’s outer membrane and then squeeze their way inside.




Once inside, the virus RNA instructs the cell’s machinery to make a long polypeptide (protein) containing special enzymes. This long protein must be cut apart to liberate the enzymes for the virus to replicate. To accomplish this, the virus also encodes a special ‘scissors’, called 3CL protease, which cleaves the polypeptide up into the different enzymes that then become functional.



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's 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.