BioInfoMiner elucidates the role of the early secretory pathway in SARS-CoV-2 infection

Here, we analyze and discuss the contribution of the molecular machines operating in the early secretory pathway in the biogenesis of SARS-CoV-2 and their relevance for potential antiviral targeting. The fact that these molecular machines are conserved throughout evolution, together with the redundancy and tissue specificity of their components, provides opportunities in the search for unique proteins essential for SARS-CoV-2 biology that could also be targeted with therapeutic objectives. Finally, we provide an overview of recent evidence implicating proteins of the early secretory pathway as potential antiviral targets with effective therapeutic applications.

The journeys of CoV-2 in the host cell. Coronavirus infection starts with the binding of the spike protein to cognate receptors. This drives conformational changes that promote fusion of the viral particle with the host cell’s plasma membrane. Once in the cytoplasm, viral particles are uncoated, and the viral RNA genome is translated, producing two polyproteins (pp1a and pp1ab). These polypeptides are proteolytically processed by host and viral proteases, generating nonstructural proteins (nsps). nsps assemble to form the replicase (R), which together with pp1a/pp1ab produces the replicase–polymerase complex. Replicase polymerase complex is responsible for the replication of the viral genome and for the production of subgenomic RNAs. The latter are translated to form structural proteins nucleocapsid (N), spike (S), membrane (M), and envelope (E). In addition to these genomic elements shared by other CoVs, the SARS-CoV-2 genome also contains eight ORFs coding for accessory proteins. Structural proteins are subjected to diverse posttranslational modifications in the ER and Golgi compartments, including disulfide bond and formation N- and O-glycosylation. Structural proteins concentrate in the ERGIC, where they assemble around the genome–nucleocapsid complexes. Mature virions are packed and budded in smooth-walled vesicles and then transported along downstream organelles of the exocytic pathway.