Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1785088261562040320 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10418426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT beegmarten acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT baronisara acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT piottiarianna acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT portaalessia acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT deluigiada acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT cagnottoalfredo acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT gobbimarco acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT diomedeluisa acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT salmonamario acomprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT beegmarten comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT baronisara comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT piottiarianna comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT portaalessia comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT deluigiada comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT cagnottoalfredo comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT gobbimarco comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT diomedeluisa comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection AT salmonamario comprehensivetechnologyplatformfortherapiddiscoveryofpeptideinhibitorsagainstsarscov2pseudovirusinfection |