Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface
Though the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular recept...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/10/8765 |
| _version_ | 1797599848034205696 |
|---|---|
| author | Kelly Bugatti Andrea Sartori Lucia Battistini Crescenzo Coppa Emiel Vanhulle Sam Noppen Becky Provinciael Lieve Naesens Annelies Stevaert Alessandro Contini Kurt Vermeire Franca Zanardi |
| author_facet | Kelly Bugatti Andrea Sartori Lucia Battistini Crescenzo Coppa Emiel Vanhulle Sam Noppen Becky Provinciael Lieve Naesens Annelies Stevaert Alessandro Contini Kurt Vermeire Franca Zanardi |
| author_sort | Kelly Bugatti |
| collection | DOAJ |
| description | Though the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular receptor ACE2. Here, we exploited the core structure of polymyxin B, a naturally occurring antibiotic, to design and synthesize unprecedented peptidomimetics (PMs), intended to target contemporarily two defined, non-overlapping regions of the S receptor-binding domain (RBD). Monomers <b>1</b>, <b>2</b>, and <b>8</b>, and heterodimers <b>7</b> and <b>10</b> bound to the S-RBD with micromolar affinity in cell-free surface plasmon resonance assays (<i>K</i><sub>D</sub> ranging from 2.31 μM to 2.78 μM for dimers and 8.56 μM to 10.12 μM for monomers). Although the PMs were not able to fully protect cell cultures from infection with authentic live SARS-CoV-2, dimer <b>10</b> exerted a minimal but detectable inhibition of SARS-CoV-2 entry in U87.ACE2<sup>+</sup> and A549.ACE2.TMPRSS2<sup>+</sup> cells. These results validated a previous modeling study and provided the first proof-of-feasibility of using medium-sized heterodimeric PMs for targeting the S-RBD. Thus, heterodimers <b>7</b> and <b>10</b> may serve as a lead for the development of optimized compounds, which are structurally related to polymyxin, with improved S-RBD affinity and anti-SARS-CoV-2 potential. |
| first_indexed | 2024-03-11T03:40:08Z |
| format | Article |
| id | doaj.art-f60413dfa7c94c51ab033a9e6be82aaf |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:40:08Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f60413dfa7c94c51ab033a9e6be82aaf2023-11-18T01:41:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012410876510.3390/ijms24108765Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 InterfaceKelly Bugatti0Andrea Sartori1Lucia Battistini2Crescenzo Coppa3Emiel Vanhulle4Sam Noppen5Becky Provinciael6Lieve Naesens7Annelies Stevaert8Alessandro Contini9Kurt Vermeire10Franca Zanardi11Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, ItalyDepartment of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, ItalyDepartment of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via Venezian 21, 20133 Milano, ItalyKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, BelgiumKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, BelgiumKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, BelgiumKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, BelgiumKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, BelgiumDepartment of Pharmaceutical Sciences, University of Milan, Via Venezian 21, 20133 Milano, ItalyKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, BelgiumDepartment of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, ItalyThough the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular receptor ACE2. Here, we exploited the core structure of polymyxin B, a naturally occurring antibiotic, to design and synthesize unprecedented peptidomimetics (PMs), intended to target contemporarily two defined, non-overlapping regions of the S receptor-binding domain (RBD). Monomers <b>1</b>, <b>2</b>, and <b>8</b>, and heterodimers <b>7</b> and <b>10</b> bound to the S-RBD with micromolar affinity in cell-free surface plasmon resonance assays (<i>K</i><sub>D</sub> ranging from 2.31 μM to 2.78 μM for dimers and 8.56 μM to 10.12 μM for monomers). Although the PMs were not able to fully protect cell cultures from infection with authentic live SARS-CoV-2, dimer <b>10</b> exerted a minimal but detectable inhibition of SARS-CoV-2 entry in U87.ACE2<sup>+</sup> and A549.ACE2.TMPRSS2<sup>+</sup> cells. These results validated a previous modeling study and provided the first proof-of-feasibility of using medium-sized heterodimeric PMs for targeting the S-RBD. Thus, heterodimers <b>7</b> and <b>10</b> may serve as a lead for the development of optimized compounds, which are structurally related to polymyxin, with improved S-RBD affinity and anti-SARS-CoV-2 potential.https://www.mdpi.com/1422-0067/24/10/8765cyclic peptidesprotein–peptide interactionsantiviral agentsdrug designreceptor-binding domain (RBD)solid-phase peptide synthesis |
| spellingShingle | Kelly Bugatti Andrea Sartori Lucia Battistini Crescenzo Coppa Emiel Vanhulle Sam Noppen Becky Provinciael Lieve Naesens Annelies Stevaert Alessandro Contini Kurt Vermeire Franca Zanardi Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface International Journal of Molecular Sciences cyclic peptides protein–peptide interactions antiviral agents drug design receptor-binding domain (RBD) solid-phase peptide synthesis |
| title | Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface |
| title_full | Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface |
| title_fullStr | Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface |
| title_full_unstemmed | Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface |
| title_short | Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface |
| title_sort | novel polymyxin inspired peptidomimetics targeting the sars cov 2 spike hace2 interface |
| topic | cyclic peptides protein–peptide interactions antiviral agents drug design receptor-binding domain (RBD) solid-phase peptide synthesis |
| url | https://www.mdpi.com/1422-0067/24/10/8765 |
| work_keys_str_mv | AT kellybugatti novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT andreasartori novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT luciabattistini novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT crescenzocoppa novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT emielvanhulle novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT samnoppen novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT beckyprovinciael novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT lievenaesens novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT anneliesstevaert novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT alessandrocontini novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT kurtvermeire novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface AT francazanardi novelpolymyxininspiredpeptidomimeticstargetingthesarscov2spikehace2interface |