Viral Replication

Viral replication of SARS-CoV-2, a positive-stranded RNA virus, takes place in the host cell cytoplasm, in close contact with intracellular membranes. The proximity of viral and host cell factors enables rapid viral reproduction and evasion of the innate immune response.

Research Areas

Mechanisms of SARS-CoV-2 Replication

Following viral cell entry and viral uncoating, the SARS-CoV-2 viral genome is translated and replicated. The virus co-opts certain host cell machinery to reproduce itself. First to be translated are two polyproteins, PP1A and PP1AB, which contain within their sequence two key viral proteases, papain-like protease (PLpro) and the coronavirus main protease (Mpro, also known as 3CLpro). PLpro and Mpro cleave other translated polyproteins into their constituent parts for viral assembly. Downstream of 1A and 1AB are genes encoding four structural proteins that form the virus coat: spike (S), envelope (E), membrane (M), and nucleocapsid (N). Once enough new viral RNA and proteins have accumulated, assembly takes place. New viral particles are released via vesicular exocytosis.

SARS CoV-2 shares 80% sequence identity homology with SARS-CoV and 50% with MERS-CoV. The SARS-Cov-2 genome consists of a single continuous RNA strand comprising 30 kb and containing 15 open reading frames (ORFs), two (1a and 1b) of which encode viral the polyproteins, which are the first products of translation.

COVID-19 Targets for Intervention

The viral replication process offers several targets for intervention, including the proteases PLpro and Mpro, and viral protease inhibitors, such as Lopinavir (Cat. No. 7052), has been shown to inhibit SARS-CoV-2 replication in vitro. Enzymes involved in replicating the viral genome, such as polymerases, are also potential targets; Remdesivir (Cat. No. 7226), an inhibitor of RNA-dependent RNA polymerase (RdRp, nsp12), has additionally been found to inhibit SARS-CoV-2 replication in vitro. Other enzymes involved in replication of the viral genome include helicase (nsp13) and 3' - 5'-exonuclease (nsp10/14), which could also be targeted. Among protein synthesis inhibitors that have been investigated, Homoharringtonine (Cat. No. 1416) and Emetine inhibit replication of SARS-CoV-2.

Research has also highlighted host proteins that interact with viral proteins as potential targets. For example, SARS-CoV-2 RNA-dependent RNA polymerase has been found to interact with receptor interacting protein kinase 1 (RIPK1), while 3' - 5'-exonuclease has been found to interact with inosine monophosphate dehydrogenase 2 (IMPDH2).