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. 2020 Jul 2;8(7):991. doi: 10.3390/microorganisms8070991

Figure 4.

Figure 4

Schematic representation of Middle East respiratory syndrome coronavirus (MERS-CoV) replication cycle and key targets for antiviral activity. The spike protein of MERS-CoV initiates host cell infection via binding its receptor-binding domain (RBD) in the S1 subunit into cellular receptor dipeptidyl peptidase 4 (DPP4), originally known as the lymphocyte cell surface protein CD26. Following binding, the viral particle in the form of an endosome internalizes into the cytosol via acid-dependent proteolytic cleavage of S protein by a cathepsin or TMPRRS2. To release the viral genome (+ssRNA) into the cytoplasm, fusion of the viral and cellular membranes within acidified endosome occurs. Initially, the replicase gene, which encodes the largest two open-reading frames “ORF1a and ORF1ab”, is translated to express two co-terminal polyproteins, pp1a and pp1ab. These polyproteins are further cleaved by virus-encoded proteases “papain-like protease PLpro and 3C-like protease 3CLpro" into 16 mature nonstructural proteins (nsp) including viral polymerase subunits. Essential elements for viral genome replication are gathered as RNA replication–transcription complexes (RTCs) within the endoplasmic reticulum-derived double-membrane vesicles (DMVs). The RTCs drive the production of intermediate negative-sense viral genome (–ssRNA) transcript. During replication, the –ssRNA genome is used as a template for generating nascent +ssRNA. Along with the continuous transcription to generate the nascent full-length coding +ssRNA, sub-genomic RNAs, including those encoding all essential structural proteins (spike (S), envelope (E), membrane (M), and nucleocapsid (N)), are produced via discontinuous transcription. Nucleocapsid and nascent genomic RNA are assembled together in the cytoplasm and further transported into the lumen of the endoplasmic reticulum (ER)–Golgi intermediate compartment (ERGIC). Meanwhile, the S, E, and M sub-genomic RNAs are translated and inserted into the membrane of the rough endoplasmic reticulum (ER), from where they are transported to interact with RNA-encapsidated N proteins in the ERGIC, forming a mature viral particle. Via exocytosis, the nascent viral particle is then released from the infected cell. The repurposed therapeutic drugs undergoing preclinical and clinical trials against MERS-CoV in the context of host pathways and virus replication mechanisms are represented in the figure. The symbol ⊣ refers to inhibition.