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Stapled ACE2 peptidomimetics designed to target the SARS-CoV-2 spike protein do not prevent virus internalization.

ABSTRACT: COVID-19 is caused by a novel coronavirus called severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Virus cell entry is mediated through a protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2). A series of stapled peptide ACE2 peptidomimetics based on the ACE2 interaction motif were designed to bind the coronavirus S-protein RBD and inhibit binding to the human ACE2 receptor. The peptidomimetics were assessed for antiviral activity in an array of assays including a neutralization pseudovirus assay, immunofluorescence (IF) assay and in-vitro fluorescence polarization (FP) assay. However, none of the peptidomimetics showed activity in these assays, suggesting that an enhanced binding interface is required to outcompete ACE2 for S-protein RBD binding and prevent virus internalization.

SUBMITTER: Morgan DC

PROVIDER: S-EPMC7883042 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Stapled ACE2 peptidomimetics designed to target the SARS-CoV-2 spike protein do not prevent virus internalization.

Morgan Danielle C DC Morris Caroline C Mahindra Amit A Blair Connor M CM Tejeda Gonzalo G Herbert Imogen I Turnbull Matthew L ML Lieber Gauthier G Willett Brian J BJ Logan Nicola N Smith Brian B Tobin Andrew B AB Bhella David D Baillie George G Jamieson Andrew G AG

Peptide science (Hoboken, N.J.) 20210108 4

COVID-19 is caused by a novel coronavirus called severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Virus cell entry is mediated through a protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2). A series of stapled peptide ACE2 peptidomimetics based on the ACE2 interaction motif were designed to bind the coronavirus S-protein RBD and inhibit binding to the human ACE2 receptor. The peptidomimetics were assessed for antiviral ac ...[more]

PMID: 33615115

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Project description:Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor that locks onto the surface spike protein of the 2002 SARS coronavirus (SARS-CoV-1) and of the novel, highly transmissible and deadly 2019 SARS-CoV-2, responsible for the COVID-19 pandemic. One strategy to avoid the virus infection is to design peptides by extracting the human ACE2 peptidase domain α1-helix, which would bind to the coronavirus surface protein, preventing the virus entry into the host cells. The natural α1-helix peptide has a stronger affinity to SARS-CoV-2 than to SARS-CoV-1. Another peptide was designed by joining α1 with the second portion of ACE2 that is far in the peptidase sequence yet grafted in the spike protein interface with ACE2. Previous studies have shown that, among several α1-based peptides, the hybrid peptidic scaffold is the one with the highest/strongest affinity for SARS-CoV-1, which is comparable to the full-length ACE2 affinity. In this work, binding and folding dynamics of the natural and designed ACE2-based peptides were simulated by the well-known coarse-grained structure-based model, with the computed thermodynamic quantities correlating with the experimental binding affinity data. Furthermore, theoretical kinetic analysis of native contact formation revealed the distinction between these processes in the presence of the different binding partners SARS-CoV-1 and SARS-CoV-2 spike domains. Additionally, our results indicate the existence of a two-state folding mechanism for the designed peptide en route to bind to the spike proteins, in contrast to a downhill mechanism for the natural α1-helix peptides. The presented low-cost simulation protocol demonstrated its efficiency in evaluating binding affinities and identifying the mechanisms involved in the neutralization of spike-ACE2 interaction by designed peptides. Finally, the protocol can be used as a computer-based screening of more potent designed peptides by experimentalists searching for new therapeutics against COVID-19.

Dataset Information

Stapled ACE2 peptidomimetics designed to target the SARS-CoV-2 spike protein do not prevent virus internalization.

Publications

Stapled ACE2 peptidomimetics designed to target the SARS-CoV-2 spike protein do not prevent virus internalization.

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