COVID-19 proteins

SARS-CoV-2, the causative virus of COVID-19, is composed of several proteins, some of them shared among several other strains of coronaviruses, such as the nucleoprotein (N-protein) and the spike protein (S-protein). COVID-19 proteins can be divided into nonstructural and structural depending on their role. Structural proteins are involved in virion assembly and infection while nonstructural proteins play a specific role in the replication of CoVs. 4 proteins are known to play a structural role:

• The S-protein (or spike protein) is responsible for the "corona" structure of the virus. The S-protein is composed of subunits S1 and S2, being responsible for binding the angiotensin converter enzyme 2 (ACE 2) receptor and for viral internalization, respectively. Due to its binding properties, it remains one of the most privileged targets for the development of new therapies against SARS-CoV-2. The affinity of COVID-19 spike protein for ACE 2 was proven to be highly superior to the one of SARS-CoV explaining the faster spreading of the disease. Within the S1 subunit, SARS-CoV-2 carries its receptor-binding domain (RBD) containing residues that bind directly to the ACE2. Due to its pivotal role in infection, strong selective pressure is exerted on the RBD, recurrently creating new variants of the virus. Recently, three emerging variants carrying RBD-located mutations were detected. They are the UK variant (B.1.1.7 lineage), South African variant (B.1.351 lineage), and the Brazilian variant (P.1 lineage). All three variants share the biologically relevant mutation N501Y known to increase SARS-CoV-2 transmissibility.
• The E-protein (or envelope protein) is a small protein composed of around 100 amino acids and a single hydrophobic domain. It is mainly involved in virion assembly by inducing membrane curvature and contributing to membrane scission.
• The N-protein packages the RNA genome in a ribonucleoprotein complex to form the nucleocapsid. In addition to its role in viral assembly, it is also known to be involved in viral RNA transcription. It is the most abundant protein in virus-infected cells, making it an interesting target for diagnostic applications.
• The M-protein is a glycoprotein composed of 3 N-terminal transmembrane domains (TM1, TM2 and TM3) and is known to play a central role in viral assembly. This protein is also reportedly involved in the suppression of the innate antiviral response by preventing type I IFN production during SARS-CoV infection. Therefore, it can also be considered as a potentially interesting target for therapeutic applications.

16 nonstructural proteins have also been identified. Even though their roles are not always fully understood, some of them remain attractive targets for therapeutic applications such as:

• The CoV nsp5 proteases which are known to process nsps at several cleavage sites. By targeting this protein, it could be possible to prevent the release of other nsps and thus completely block viral replication.
• Nsp3 and, more specifically, the PLPro domain (papain like proteinase) is also known to be involved in the coronaviral replication thanks to its ability to process the viral polyprotein. In addition, this domain presents deubiquitinating and deISGylating activity in SARS-CoV leading to innate immunity suppression.

Lessons learned during the previous SARS and MERS outbreak provided valuable information about the role of the different proteins. However, efforts are still needed to develop efficient diagnostic and therapeutic tools to mitigate the spread of the SARS-CoV-2 pandemic. For this reason, ProteoGenix is working on a constantly evolving catalog of ready-to-use COVID-19 proteins to accelerate all the SARS-related research projects.