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Interaction of severe acute respiratory syndrome-coronavirus and NL63 coronavirus spike proteins with angiotensin converting enzyme-2.

ABSTRACT: Although in different groups, the coronaviruses severe acute respiratory syndrome-coronavirus (SARS-CoV) and NL63 use the same receptor, angiotensin converting enzyme (ACE)-2, for entry into the host cell. Despite this common receptor, the consequence of entry is very different; severe respiratory distress in the case of SARS-CoV but frequently only a mild respiratory infection for NL63. Using a wholly recombinant system, we have investigated the ability of each virus receptor-binding protein, spike or S protein, to bind to ACE-2 in solution and on the cell surface. In both assays, we find that the NL63 S protein has a weaker interaction with ACE-2 than the SARS-CoV S protein, particularly in solution binding, but the residues required for contact are similar. We also confirm that the ACE-2-binding site of NL63 S lies between residues 190 and 739. A lower-affinity interaction with ACE-2 might partly explain the different pathological consequences of infection by SARS-CoV and NL63.

SUBMITTER: Mathewson AC

PROVIDER: S-EPMC2886958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe COVID-19 pandemic has killed over 6 million people worldwide. Despite the accumulation of knowledge about the causative pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathogenesis of this disease, cures remain to be discovered. We searched for certain peptides that might interfere with spike protein (S protein)-angiotensin-converting enzyme 2 (ACE2) interactions.MethodsPhage display (PhD)-12 peptide library was screened against recombinant spike trimer (S-trimer) or receptor-binding domain (S-RBD) proteins. The resulting enriched peptide sequences were obtained, and their potential binding sites on S-trimer and S-RBD 3D structure models were searched. Synthetic peptides corresponding to these and other reference sequences were tested for their efficacy in blocking the binding of S-trimer protein onto recombinant ACE2 proteins or ACE2-overexpressing cells.ResultsAfter three rounds of phage selections, two peptide sequences (C2, DHAQRYGAGHSG; C6, HWKAVNWLKPWT) were enriched by S-RBD, but only C2 was present in S-trimer selected phages. When the 3D structures of static monomeric S-RBD (6M17) and S-trimer (6ZGE, 6ZGG, 7CAI, and 7CAK, each with different status of S-RBDs in the three monomer S proteins) were scanned for potential binding sites of C2 and C6 peptides, C6 opt to bind the saddle of S-RBD in both 6M17 and erected S-RBD in S-trimers, but C2 failed to cluster there in the S-trimers. In the competitive S-trimer-ACE2-binding experiments, synthetic C2 and C6 peptides inhibited S-trimer binding onto 293T-ACE2hR cells at high concentrations (50 μM) but not at lower concentrations (10 μM and below), neither for the settings of S-trimer binding onto recombinant ACE2 proteins.ConclusionUsing PhD methodology, two peptides were generated bearing potentials to interfere with S protein-ACE2 interaction, which might be further exploited to produce peptidomimetics that block the attachment of SARS-CoV-2 virus onto host cells, hence diminishing the pathogenesis of COVID-19.

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Interaction of severe acute respiratory syndrome-coronavirus and NL63 coronavirus spike proteins with angiotensin converting enzyme-2.

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