New insights may reshape strategies to manage COVID-19 infection
Oeiras, 23rd June 2025
SARS-CoV-2, the COVID-19 virus, contains a RNA genome and multiple proteins, including the nucleocapsid (N) protein. The N protein is essential for RNA binding and packaging, as well as for mediating interactions inside host cells. For these reasons, it has emerged as a promising therapeutic target in antiviral intervention.
To ensure efficient genomic RNA organization and replication, SARS-CoV-2 forms membraneless organelles within infected host cells, known as biomolecular condensates. These condensates are like microscopic “droplets” made up of multiple N proteins and viral RNA that separate from the rest of the cell's contents.
In a recent study published in Nucleic Acids Research, ITQB NOVA researchers have revealed key structural determinants of the N protein that underpin how these condensates form and influence critical stages of the viral life cycle.
The N protein consists of several functional domains, including an intrinsically disordered linker (IDL) region that is flexible and mediates interactions with other proteins. The research team identified a coiled-coil motif within IDL, i.e. a spiral structure, which allows multiple N proteins to bind to each other, forming complexes. “The more N proteins come together, thanks to IDL, the more likely they are to form biomolecular condensates,” explains Tiago Cordeiro, leader of the Dynamic Structural Biology laboratory at ITQB NOVA.
“We found that this short ‘molecular velcro’ within the N protein binds identical proteins together, forming larger aggregates and droplets with liquid-like properties, which the virus depends on to package its RNA”, adds Tiago Gomes, a researcher at ITQB NOVA.
These interactions between N proteins are dynamic and adapt to the cell's environment. Depending on the concentration or presence of RNA, the N protein can change shape and bind to one, two or three other proteins.
“When we introduced mutations that disrupt this motif, the ability of the protein to engage in these critical interactions was compromised, impairing condensate formation and altering their size, stability, and flow within cells. This ultimately affects key viral processes such as RNA packaging and interactions with the host cell”, notes Guillem Hernandez, researcher at ITQB NOVA and first author of the study.
In sum, the IDL functions as a regulatory switch that modulates essential steps of the viral replication cycle. “Targeting this molecular switch may offer a new avenue to inhibit SARS-CoV-2 infection, making the IDL a compelling target for antiviral drug development”, concludes Tiago Cordeiro.
