Figure 2: Virus-based and host-based treatment options targeting the coronavirus replication cycle.
From: Coronaviruses — drug discovery and therapeutic options
Binding between the receptor-binding domain on the S1 subunit of spike glycoprotein (S) and the host receptor triggers conformational changes in the S2 subunit of S. This leads to fusion of the viral and cell membranes. Coronaviruses (CoVs) enter the host cell using the endosomal pathway and/or the cell surface non-endosomal pathway. Endosomal cell entry of CoVs is facilitated by low pH and the pH-dependent endosomal cysteine protease cathepsins. S is activated and cleaved into the S1 and S2 subunits by other host proteases, such as transmembrane protease serine 2 (TMPRSS2) and TMPRSS11D, which enables cell surface non-endosomal virus entry at the plasma membrane. Middle East respiratory syndrome (MERS)-CoV S is additionally activated by the serine endoprotease furin. CoVs then dissemble intracellularly to release the nucleocapsid and viral RNA into the cytoplasm for the translation of ORF1a/b into the large replicase polyprotein 1a (pp1a) and pp1ab and for the replication of genomic RNA. pp1a and pp1ab are cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce non-structural proteins (NSPs), including RNA-dependent RNA polymerase (RdRp) and helicase, which are involved in the transcription and replication of the virus. The NSPs produced by the cleavage of pp1a and pp1ab form the replication–transcription complex. Attachment of the hydrophobic domains of the CoV replication–transcription complex to the limiting membrane derived from the endoplasmic reticulum (ER) produces typical CoV replication structures including double-membrane vesicles and convoluted membranes. The full-length positive-strand genomic RNA is transcribed to form a full-length negative-strand template for synthesis of new genomic RNAs and overlapping subgenomic negative-strand templates. Subgenomic mRNAs are then synthesized and translated to produce the structural and accessory proteins. The helical nucleocapsid formed by the assembly of nucleocapsid protein (N) and genomic RNA interacts with the other structural proteins to form the assembled virion, which is then released by exocytosis into the extracellular compartment. Virus- and host-based treatment options are highlighted in red and blue, respectively. +, positive-strand RNA; −, negative-strand RNA; AP, accessory protein; CYP, cyclophilin; dec-RVKR-CMK, decanoyl-Arg-Val-Lys-Arg-chloromethylketone; DRACO, double-stranded RNA-activated caspase oligomerizer; E, envelope protein; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum Golgi intermediate compartment; ERK, extracellular signal-regulated kinase; M, membrane; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; N, nucleocapsid protein; NAAE, N-(2-aminoethyl)-1-aziridine-ethanamine; NFAT, nuclear factor of activated T cells; ORF, open reading frame; PI3K, phosphoinositide 3-kinase; poly(I:C), polyinosinic:polycytidylic acid; RdRp, RNA-dependent RNA polymerase; S, spike glycoprotein; SARS-CoV, severe acute respiratory syndrome coronavirus; siRNA, small interfering RNA. *Only siRNAs that have been evaluated in published reports are included. siRNAs directed against other parts of the CoV genome would also be expected to diminish the accumulation or translation of genomic and all upstream subgenomic RNAs. Adapted with permission from Ref. 9, American Society for Microbiology.
