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. 2020 Nov 23;44(1 Suppl 1):e20200212.
doi: 10.1590/1678-4685-GMB-2020-0212. eCollection 2020.

Molecular mechanisms and pharmacological interventions in the replication cycle of human coronaviruses

Fernando Moreira Simabuco  1 , Rodrigo Esaki Tamura  2 , Isadora Carolina Betim Pavan  1   3 , Mirian Galliote Morale  4 , Armando Morais Ventura  5
Affiliations

Molecular mechanisms and pharmacological interventions in the replication cycle of human coronaviruses

Fernando Moreira Simabuco et al. Genet Mol Biol. .

Abstract

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), as well as SARS-CoV from 2003 along with MERS-CoV from 2012, is a member of the Betacoronavirus genus of the Nidovirales order and is currently the cause of the pandemic called COVID-19 (or Coronavirus disease 2019). COVID-19, which is characterized by cough, fever, fatigue, and severe cases of pneumonia, has affected more than 23 million people worldwide until August 25th, 2020. Here, we present a review of the cellular mechanisms associated with human coronavirus replication, including the unique molecular events related to the replication transcription complex (RTC) of coronaviruses. We also present information regarding the interactions between each viral protein and cellular proteins associated to known host-pathogen implications for the coronavirus biology. Finally, a specific topic addresses the current attempts for pharmacological interventions against COVID-19, highlighting the possible effects of each drug on the molecular events of viral replication. This review intends to aid future studies for a better understanding of the SARS-CoV-2 replication cycle and the development of pharmacological approaches targeting COVID-19.

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Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Molecular mechanisms related to the production of non-structural proteins (nsps) and assembly of the SARS-CoV-2 replication and transcription complex (RTC). Process 1: after recognition of the ACE2 (Angiotensin Converting Enzyme 2) cell receptor, the viral nucleocapsid is released into the cytoplasm by endocytosis, or fusion of the viral envelope, with the cell membrane. Process 2: the translation of the pp1a and pp1b genes from the 5’-capped and 3’-polyadenylated genome (+) of the virus produces the pp1a or pp1ab polyproteins, the latter being generated by a -1 frameshift of ribosomes. These polyproteins are then cleaved by viral proteases generating 16 virus nonstructural proteins (nsps), some of which are used to assemble the RTC, including the RNA-dependent RNA polymerase (RdRp or nsp12). Pharmacological interventions targeting specific points of the replication cycle of coronaviruses are highlighted. RTC: Replication and transcription complex; RdRp: RNA-dependent RNA polymerase.
Figure 2
Figure 2. Molecular events related to the expression of structural proteins, replication of the genome, and assembly of the SARS-CoV-2. Processes 1a and 1b: the synthesis of RNA (-) by RTC, initiated in the 3’ anti-leader sequence of the genome (+), may occur continuously, generating a complete copy of the genome called antigenome (-). The antigenome is then used by RTC to produce multiple copies of the genome (+). Processes 2a and 2b: RNA synthesis by RTC may, however, be temporarily interrupted when a TRS is copied. The newly synthesized RNA (-) is then transferred to the 5’ end of the genome, where the complementarity of sequences allows the RNA (-) synthesis to continue in the leader TRS, merging the sequences between body and leader TRSs. In turn, these subgenomic chimeric RNAs (-) serve as templates for the continuous synthesis of subgenomic mRNAs (+). Process 3: the structural S, E, M, and N proteins are then translated from the 3’-co-lateral subgenomic mRNAs (+), where S, E, and M proteins are produced in the rough endoplasmic reticulum. Process 4: the N protein produced in the cytosol interacts with the viral genome (+), forming the nucleocapsid. Process 5: membrane proteins S, M, and E then interact with viral nucleocapsids to form virions in the ERGIC. Process 6: finally, the virions are externalized from the cell by exocytosis via the Golgi pathway. TRS: Transcriptional Regulatory Sequences; ER: endoplasmic reticulum; RTC: Replication Transcription Complex. ERGIC: Endoplasmic Reticulum - Golgi Intermediate Compartment.
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