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Review
. 2017 Feb;21(2):131-143.
doi: 10.1080/14728222.2017.1271415. Epub 2016 Dec 21.

MERS-CoV spike protein: a key target for antivirals

Lanying Du  1 , Yang Yang  2 , Yusen Zhou  3 , Lu Lu  4 , Fang Li  2 , Shibo Jiang  1   4
Affiliations
Review

MERS-CoV spike protein: a key target for antivirals

Lanying Du et al. Expert Opin Ther Targets. 2017 Feb.

Abstract

The continual Middle East respiratory syndrome (MERS) threat highlights the importance of developing effective antiviral therapeutics to prevent and treat MERS coronavirus (MERS-CoV) infection. A surface spike (S) protein guides MERS-CoV entry into host cells by binding to cellular receptor dipeptidyl peptidase-4 (DPP4), followed by fusion between virus and host cell membranes. MERS-CoV S protein represents a key target for developing therapeutics to block viral entry and inhibit membrane fusion. Areas covered: This review illustrates MERS-CoV S protein's structure and function, particularly S1 receptor-binding domain (RBD) and S2 heptad repeat 1 (HR1) as therapeutic targets, and summarizes current advancement on developing anti-MERS-CoV therapeutics, focusing on neutralizing monoclonal antibodies (mAbs) and antiviral peptides. Expert opinion: No anti-MERS-CoV therapeutic is approved for human use. Several S-targeting neutralizing mAbs and peptides have demonstrated efficacy against MERS-CoV infection, providing feasibility for development. Generally, human neutralizing mAbs targeting RBD are more potent than those targeting other regions of S protein. However, emergence of escape mutant viruses and mAb's limitations make it necessary for combining neutralizing mAbs recognizing different neutralizing epitopes and engineering them with improved efficacy and reduced cost. Optimization of the peptide sequences is expected to produce next-generation anti-MERS-CoV peptides with improved potency.

Keywords: MERS; MERS-CoV; membrane fusion; monoclonal antibodies; peptides; receptor-binding domain; spike protein; therapeutics.

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Conflict of interest statement

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1
Figure 1
Schematic diagram of MERS-CoV life cycle [8,39,42,43]. MERS-CoV binds to its cellular receptor DPP4 via the S protein and then enters target cells, followed by fusion of the cell and virus membranes and release of the viral RNA genome into the cytoplasm. The open reading frame (ORF), 1a and 1b, in the viral genomic RNA is translated into replicase polyproteins pp1a and pp1ab, respectively, and then potentially cleaved by papain-like protease (PLpro), 3 C-like cysteine protease (3CLpro, main protease), and other viral proteinases into 16 nonstructural proteins (nsp1–16). A negative-strand genomic-length RNA is synthesized as the template for replicating viral genomic RNA. Negative-strand subgenome-length mRNAs (sg mRNAs) are formed from the viral genome as discontinuous RNAs and used as the template to transcribe sg mRNAs. Viral N protein is assembled with the genomic RNA in the cytoplasm. The synthesized S, M and E proteins are gathered in the endoplasmic reticulum (ER) and transported to the ER-Golgi intermediate compartment (ERGIC) where they interact with the RNA-N complex and assemble into viral particles. The viral particles are maturated in the Golgi body and then released from the cells.
Figure 2
Figure 2
Functional domains of MERS-CoV S protein and structural basis of MERS-CoV receptor binding [49,51,52]. (a) Schematic diagram of MERS-CoV S protein. S contains S1 and S2 subunits. SP, signal peptide; RBD, receptor-binding domain; RBM, receptor-binding motif; FP, fusion peptide; HR1 and HR2, heptad repeat region 1 and 2; TM, transmembrane; CP, cytoplasmic tail. (b) Crystal structure of MERS-CoV RBD. Core structure is in purple, and RBM is in cyan (PDB ID: 4KQZ). The two N-linked glycans are labeled in black. (c) Crystal structure of MERS-CoV RBD in complex with its receptor human hDPP4 (orange) (PDB ID: 4KR0). Contacting residues in RBM are shown as yellow sticks and labeled in black. Full color available online.
Figure 3
Figure 3
Schematic diagrams of MERS-CoV S protein S2-mediated membrane fusion and MERS-CoV S-targeting mAbs and peptides [59,61]. (a) Schematic diagram of MERS-CoV S2-mediated membrane fusion. The following major processes are involved in MERS-CoV membrane fusion. In receptor binding stage, S protein, which exists as a trimer, binds to the cellular receptor DPP4 via S1-RBD. This binding triggers conformational changes of S protein, leading to dissociation of S1 from S2 with exposed HR1-trimer and HR2-trimer, thus entering intermediate (pre-hairpin) stage. In fusion (hairpin) stage, HR1 and HR2 helices associate with each other to form a 6-helix bundle (6-HB) fusion core, and bring the membranes of virus and cell into close proximity for fusion. (b) Schematic diagram of mechanism of action of MERS-CoV S1-RBD-targeting neutralizing mAbs and S2-HR1-targeting peptides. The RBD-specific antibody (IgG or Fab) binds to viral S1-RBD and interrupts the binding between RBD and DPP4, thus blocking virus infection. HR1-targeting HR2 peptide (e.g. HR2P) binds to the HR1-trimer to form a heterologous 6-HB, thus interferes with subsequent 6-HB fusion core formation and virus-cell membrane fusion, resulting in the inhibition of MERS-CoV infection.
Figure 4
Figure 4
Structural basis of MERS-CoV infection inhibited by RBD-specific neutralizing antibodies [61,69,71,74]. (a) Crystal structures of MERS-CoV RBD in complex with mouse neutralizing mAb 4C2-Fab (PDB ID: 5DO2) or D12-Fab (PDB ID: 4ZPT). Crystal structures of RBD in complex with human neutralizing mAbs MERS-27-Fab (PDB ID: 4ZS6) (b) and m336-Fab (PDB ID: 4XAK) (c). MERS-CoV RBD core structure is colored purple, and RBM is in cyan. The mAb-Fab light (L) and heavy (H) chains are in red and green, respectively. VH, CH, VL, and CL indicate variable heavy, constant heavy, variable light, and constant light chains, respectively. Contacting residues at the RBD-binding interface in Fab-VL and VH chains are shown as blue and magenta sticks, respectively, and those in RBM are shown as yellow sticks. Contacting residues in the RBM involved in both human hDPP4-binding and Fab-binding are labeled in red, and the selected RBD residues at the Fab-binding interface are in black. Full color available online.
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