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

Morgan, D. C. et al. (2021) Stapled ACE2 peptidomimetics designed to target the SARS-CoV-2 spike protein do not prevent virus internalisation. Peptide Science, 113(4), e24217. (doi: 10.1002/pep2.24217) (PMID:33615115) (PMCID:PMC7883042)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Baillie, Professor George and Willett, Professor Brian and Herbert, Miss Imogen and Blair, Dr Connor and Mahindra, Dr Amit and Bhella, Professor David and Turnbull, Dr Matthew and Morgan, Dr Danielle and Jamieson, Professor Andrew and Smith, Dr Brian and Morris, Dr Caroline and Tejeda, Dr Gonzalo and Logan, Miss Nicola and Tobin, Andrew and Lieber, Mr Gauthier
• Authors: Morgan, D. C., Morris, C., Mahindra, A., Blair, C. M., Tejeda, G., Herbert, I., Turnbull, M. L., Lieber, G., Willett, B. J., Logan, N., Smith, B., Tobin, A. B., Bhella, D., Baillie, G. S., and Jamieson, A. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Science and Engineering > School of Chemistry; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Peptide Science
• Publisher: Wiley
• ISSN: 2475-8817
• ISSN (Online): 2475-8817
• Published Online: 08 January 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Peptide Science 113(4): e24217
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
305807		Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome	Andrew Jamieson	Engineering and Physical Sciences Research Council (EPSRC)	EP/N034260/2	Chemistry
172865		EPSRC DTP 16/17 and 17/18	Tania Galabova	Engineering and Physical Sciences Research Council (EPSRC)	EP/N509668/1	Research and Innovation Services
305200		DTP 2018-19 University of Glasgow	Mary Beth Kneafsey	Engineering and Physical Sciences Research Council (EPSRC)	EP/R513222/1	MVLS - Graduate School