Researchers Discover COVID-19's "Achilles Heel"

This work was done on bacteria, but the same principle was applied to the molecule that justified thestudy published in the journal Nucleic Acids Research on June 24th . "No one had studied the N protein in depth before," admits Tiago Cordeiro, while showing Observador a presentation he was preparing for a scientific outreach conference.

In more practical terms, what happens in the transmission and infection process of these coronaviruses is as follows: the virus enters through the host's mouth or nose and, thanks to the Spike protein , has the ability to lodge and enter specific cells in the respiratory tract. It is within these cells that the virus releases its viral load—its RNA—to produce other viruses that then spread throughout the body's cells and are eventually transmitted to other people. This RNA is only organized within the virus due to the activity of the N protein.

While the Spike (S) and the other two structural proteins of this virus family—Membrane (M) and Envelope (E)—are found on the outside of the capsule, the Nucleocapsid (N) resides inside, harboring the genetic information of each of these viruses. Thus, the N protein, in addition to being responsible for protecting the RNA, ends up being the most important protein for ensuring its replication—" without the N protein, there is no virus replication "—and, consequently, the proliferation of viral material by the cells of the infected organism.

“What was well known [before the Portuguese investigation] were these two structures,” continues Tiago Cordeiro, pointing to the two “domains” colored orange and purple, respectively, on a poster that is posted on the wall of his office.

The orange color represents the NTD (N-terminal domain), the component responsible for binding the molecule to RNA. At the other end of the protein is the CTD (C-terminal domain), which, in addition to contributing to this binding, also provides other features that contribute to the protein's structure and activity. Between these two domains, however, lies another molecule that, until then, was seen only as a connector between the NTD and the CTD. However, the Portuguese research team realized that this small structure could prove to be the breakthrough of their investigation.

The official name is intrinsically disordered linker (IDL) , meaning it's an intrinsically disordered connector that allows other proteins to interact, specifically allowing multiple N proteins to bind together, forming complexes. They then discovered that this "little Velcro" in the protein's structure connects several identical molecules together, forming larger aggregates and "droplets"—between the liquid and the gel—which the virus relies on to organize its RNA inside the capsule.

After in-depth investigation into the structure of this protein, an experimental question arose: "What happens if we disrupt this connector?" What they discovered by removing three specific amino acids (leucines) from its composition was that the helix structure of IDL would no longer be able to form these complexes, affecting their size and stability, as well as the essential activity of the virus, which falls under the responsibility of the N protein: the packaging and replication of the viral genetic material.