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A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection

We developed and validated a technology platform for designing and testing peptides inhibiting the infectivity of SARS-CoV-2 spike protein-based pseudoviruses. This platform integrates target evaluation, in silico inhibitor design, peptide synthesis, and efficacy screening. We generated a cyclic pep...

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Detalles Bibliográficos
Autores principales: Beeg, Marten, Baroni, Sara, Piotti, Arianna, Porta, Alessia, De Luigi, Ada, Cagnotto, Alfredo, Gobbi, Marco, Diomede, Luisa, Salmona, Mario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418426/
https://www.ncbi.nlm.nih.gov/pubmed/37569522
http://dx.doi.org/10.3390/ijms241512146
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author Beeg, Marten
Baroni, Sara
Piotti, Arianna
Porta, Alessia
De Luigi, Ada
Cagnotto, Alfredo
Gobbi, Marco
Diomede, Luisa
Salmona, Mario
author_facet Beeg, Marten
Baroni, Sara
Piotti, Arianna
Porta, Alessia
De Luigi, Ada
Cagnotto, Alfredo
Gobbi, Marco
Diomede, Luisa
Salmona, Mario
author_sort Beeg, Marten
collection PubMed
description We developed and validated a technology platform for designing and testing peptides inhibiting the infectivity of SARS-CoV-2 spike protein-based pseudoviruses. This platform integrates target evaluation, in silico inhibitor design, peptide synthesis, and efficacy screening. We generated a cyclic peptide library derived from the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor. The cell-free validation process by ELISA competition assays and Surface Plasmon Resonance (SPR) studies revealed that the cyclic peptide c9_05, but not its linear form, binds well to ACE2. Moreover, it effectively inhibited the transduction in HEK293, stably expressing the human ACE2 receptor of pseudovirus particles displaying the SARS-CoV-2 spike in the Wuhan or UK variants. However, the inhibitory efficacy of c9_05 was negligible against the Omicron variant, and it failed to impede the entry of pseudoviruses carrying the B.1.351 (South African) spike. These variants contain three or more mutations known to increase affinity to ACE2. This suggests further refinement is needed for potential SARS-CoV-2 inhibition. Our study hints at a promising approach to develop inhibitors targeting viral infectivity receptors, including SARS-CoV-2’s. This platform also promises swift identification and evaluation of inhibitors for other emergent viruses.
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spelling pubmed-104184262023-08-12 A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection Beeg, Marten Baroni, Sara Piotti, Arianna Porta, Alessia De Luigi, Ada Cagnotto, Alfredo Gobbi, Marco Diomede, Luisa Salmona, Mario Int J Mol Sci Article We developed and validated a technology platform for designing and testing peptides inhibiting the infectivity of SARS-CoV-2 spike protein-based pseudoviruses. This platform integrates target evaluation, in silico inhibitor design, peptide synthesis, and efficacy screening. We generated a cyclic peptide library derived from the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor. The cell-free validation process by ELISA competition assays and Surface Plasmon Resonance (SPR) studies revealed that the cyclic peptide c9_05, but not its linear form, binds well to ACE2. Moreover, it effectively inhibited the transduction in HEK293, stably expressing the human ACE2 receptor of pseudovirus particles displaying the SARS-CoV-2 spike in the Wuhan or UK variants. However, the inhibitory efficacy of c9_05 was negligible against the Omicron variant, and it failed to impede the entry of pseudoviruses carrying the B.1.351 (South African) spike. These variants contain three or more mutations known to increase affinity to ACE2. This suggests further refinement is needed for potential SARS-CoV-2 inhibition. Our study hints at a promising approach to develop inhibitors targeting viral infectivity receptors, including SARS-CoV-2’s. This platform also promises swift identification and evaluation of inhibitors for other emergent viruses. MDPI 2023-07-29 /pmc/articles/PMC10418426/ /pubmed/37569522 http://dx.doi.org/10.3390/ijms241512146 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Beeg, Marten
Baroni, Sara
Piotti, Arianna
Porta, Alessia
De Luigi, Ada
Cagnotto, Alfredo
Gobbi, Marco
Diomede, Luisa
Salmona, Mario
A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection
title A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection
title_full A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection
title_fullStr A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection
title_full_unstemmed A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection
title_short A Comprehensive Technology Platform for the Rapid Discovery of Peptide Inhibitors against SARS-CoV-2 Pseudovirus Infection
title_sort comprehensive technology platform for the rapid discovery of peptide inhibitors against sars-cov-2 pseudovirus infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418426/
https://www.ncbi.nlm.nih.gov/pubmed/37569522
http://dx.doi.org/10.3390/ijms241512146
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