Structures and thereby preorganizing them into their bound conformations Is a key technique for constraining short peptides in α-helical Peptide stapling based on different macrocyclization Protein, which, in turn, retards its binding to partner NHR helices. Owing to the lack of structural reinforcement provided by the parent This short CHR peptide alone does not retain its native conformation Is an important recognition motif for MERS-CoV fusion core formation, 11, 16 Although the typical α-helical region Region of the MERS-CoV CHR domain sequence showed no anti-MERS-CoVĪctivity. 14, 15 It was disappointing that a synthetic peptide spanning the α-helical Mimicking the lengthy C-terminal helices of HIV was identified as 12, 13 With this strategy, a family of decoy α-helices structurally Promising approach to inhibit membrane fusion and viral infection. Peptides that target the transiently exposed NHR coiled coil is a Sequence in MERS-CoV CHR is highlighted in red.īlocking α-helix-mediated NHR/CHR interactions using The dashed lines between the NHR and CHR domains indicate the interactionīetween the residues located at the a– d positions in the CHR and the e– g positions in the NHR to form the 6HB. (C) Interactionīetween the NHR and CHR peptides, as well as the designed P21 peptide. In the CHR, the residues at the a– d positions (yellow) in directĬontact with the NHR domains are buried in the 6HB. Only a short helical domain is found within the MERS-CoV CHR (PDB 4NJL). In the HIV 6HB structure (PDB 1AIK), the CHR segmentsįorm regular helices that pack against the central NHR core. HIV 6HBs, in which the NHR trimers and CHR segments are colored in
(A) Cartoon representations of the MERS-CoV and The NHR trimers have ∼21 helical turns, whereas the centralĬHR helices are limited to ∼4.5 turns within the longer heptad-repeatĬrystal structure of the MERS-CoV six-helix bundle (6HB)Ĭore and the design of peptides based on the interaction between the In the length of its NHR and CHR helices.
Of the Coronaviridae family, encode a notable dimorphism Viruses, including Middle East respiratory syndrome coronavirus (MERS-CoV) 5, 6 In contrast, some other class I enveloped Portion of the CHR domain displays dramatic differences in length.įor example, the fusion core structure of HIV, a Retroviridae family member, contains regular α-helical CHR domains involvingĪpproximately 10 helical turns that bind to the central trimeric NHR Of the fusion-promoting hexameric helical scaffold, their α-helical 3, 4 Despite the topologically similar conformation Grooves on the periphery of an internal three-stranded coiled coilįormed by the N-terminal heptad repeat (NHR) region of those fusion Zips up into three α-helices along the conserved hydrophobic 1, 2 In the 6-HB viral fusion apparatus, theĬ-terminal heptad repeat (CHR) segment of the trimeric virus glycoproteins Proteins, such as those of the corona-, retro-,įilo-, orthomyxo-, and paramyxoviruses, share similarities in theirĪpparent use of a trimer of α-helical hairpins, or six-helixīundle (6-HB), to mediate membrane fusion processes of virus to targetĬell. Suggesting strong potential for development as an anti-MERS-CoV therapeutic. P21S10 exhibits improved pharmacokinetic properties than HR2P-M2, Peptide P21S10 could effectively inhibit infection by MERS-CoV pseudovirusĪnd its spike protein-mediated cell–cell fusion additionally, Structure remarkably improves antiviral potency. Helical portion-based peptide to reinforce its bioactive secondary We describe that appropriate all-hydrocarbon stapling of the short Has been thwarted by the loss of the peptide’s native α-helicalĬonformation when taken out of the parent protein structure. Of Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein Such peptide mimicry of the short α-helical region in the CHR The viral and cellular membranes and provides a clear starting pointįor molecular mimicry that drives viral fusion inhibitor design. And N-terminal heptad repeat (CHR and NHR) regions of class I viralįusion proteins plays an important role in mediating the fusion of
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