Unprecedented selectivity for homologous lectin targets

DC-SIGN (CD209) and L-SIGN (CD209L) are two C-type lectin receptors (CLRs) that facilitate SARS-CoV-2 infections as viral co-receptors. SARS-CoV-2 manipulates both DC-SIGN and L-SIGN for enhanced infection, leading to interest in developing receptor antagonists. Despite their structural similarity (...

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Autores: Delaunay, Clara, Pollastri, Sara, Thepaut, Michel, Cavazzoli, Gianluca, Belvisi, Laura, Bouchikri, Clementine, Labiod, Nuria, Lasala, Fatima, Gimeno, Ana, Franconetti, Antonio|||0000-0002-7972-8795, Jiménez Barbero, Jesús|||0000-0001-5421-8513, Arda, Ana, Delgado, Rafael, Bernardi, Anna, Fieschi, Franck
Formato: artículo
Fecha de publicación:2024
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:321730
Acesso em linha:https://ddd.uab.cat/record/321730
https://dx.doi.org/urn:doi:10.1039/d4sc02980a
Access Level:acceso abierto
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spelling Unprecedented selectivity for homologous lectin targetsdifferential targeting of the viral receptors L-SIGN and DC-SIGNDelaunay, ClaraPollastri, SaraThepaut, MichelCavazzoli, GianlucaBelvisi, LauraBouchikri, ClementineLabiod, NuriaLasala, FatimaGimeno, AnaFranconetti, Antonio|||0000-0002-7972-8795Jiménez Barbero, Jesús|||0000-0001-5421-8513Arda, AnaDelgado, RafaelBernardi, AnnaFieschi, FranckDC-SIGN (CD209) and L-SIGN (CD209L) are two C-type lectin receptors (CLRs) that facilitate SARS-CoV-2 infections as viral co-receptors. SARS-CoV-2 manipulates both DC-SIGN and L-SIGN for enhanced infection, leading to interest in developing receptor antagonists. Despite their structural similarity (82% sequence identity), they function differently. DC-SIGN, found in dendritic cells, shapes the immune response by recognizing pathogen-associated carbohydrate patterns. In contrast, L-SIGN, expressed in airway epithelial endothelial cells, is not directly involved in immunity. COVID-19's primary threat is the hyperactivation of the immune system, potentially reinforced if DC-SIGN engages with exogenous ligands. Therefore, L-SIGN, co-localized with ACE2-expressing cells in the respiratory tract, is a more suitable target for anti-adhesion therapy. However, designing a selective ligand for L-SIGN is challenging due to the high sequence identity of the Carbohydrate Recognition Domains (CRDs) of the two lectins. We here present Man84, a mannose ring modified with a methylene guanidine triazole at position 2. It binds L-SIGN with a KD of 12.7μM ± 1 μM (ITC) and is the first known L-SIGN selective ligand, showing 50-fold selectivity over DC-SIGN (SPR). The X-ray structure of the L-SIGN CRD/Man84 complex reveals the guanidinium group's role in achieving steric and electrostatic complementarity with L-SIGN. This allows us to trace the source of selectivity to a single amino acid difference between the two CRDs. NMR analysis confirms the binding mode in solution, highlighting Man84's conformational selection upon complex formation. Dimeric versions of Man84 achieve additional selectivity and avidity in the low nanomolar range. These compounds selectively inhibit L-SIGN dependent trans-infection by SARS-CoV-2 and Ebola virus. Man84 and its dimeric constructs display the best affinity and avidity reported to date for low-valency glycomimetics targeting CLRs. They are promising tools for competing with SARS-CoV-2 anchoring in the respiratory tract and have potential for other medical applications. 22024-01-0120242024-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/321730https://dx.doi.org/urn:doi:10.1039/d4sc02980areponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 CB21/13/00039Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 FIS/PI21/00989European Commission https://doi.org/10.13039/501100000780 101137157European Commission https://doi.org/10.13039/501100000780 101145709Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 CEX2021-001136-Sopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3217302026-06-06T12:50:31Z
dc.title.none.fl_str_mv Unprecedented selectivity for homologous lectin targets
differential targeting of the viral receptors L-SIGN and DC-SIGN
title Unprecedented selectivity for homologous lectin targets
spellingShingle Unprecedented selectivity for homologous lectin targets
Delaunay, Clara
title_short Unprecedented selectivity for homologous lectin targets
title_full Unprecedented selectivity for homologous lectin targets
title_fullStr Unprecedented selectivity for homologous lectin targets
title_full_unstemmed Unprecedented selectivity for homologous lectin targets
title_sort Unprecedented selectivity for homologous lectin targets
dc.creator.none.fl_str_mv Delaunay, Clara
Pollastri, Sara
Thepaut, Michel
Cavazzoli, Gianluca
Belvisi, Laura
Bouchikri, Clementine
Labiod, Nuria
Lasala, Fatima
Gimeno, Ana
Franconetti, Antonio|||0000-0002-7972-8795
Jiménez Barbero, Jesús|||0000-0001-5421-8513
Arda, Ana
Delgado, Rafael
Bernardi, Anna
Fieschi, Franck
author Delaunay, Clara
author_facet Delaunay, Clara
Pollastri, Sara
Thepaut, Michel
Cavazzoli, Gianluca
Belvisi, Laura
Bouchikri, Clementine
Labiod, Nuria
Lasala, Fatima
Gimeno, Ana
Franconetti, Antonio|||0000-0002-7972-8795
Jiménez Barbero, Jesús|||0000-0001-5421-8513
Arda, Ana
Delgado, Rafael
Bernardi, Anna
Fieschi, Franck
author_role author
author2 Pollastri, Sara
Thepaut, Michel
Cavazzoli, Gianluca
Belvisi, Laura
Bouchikri, Clementine
Labiod, Nuria
Lasala, Fatima
Gimeno, Ana
Franconetti, Antonio|||0000-0002-7972-8795
Jiménez Barbero, Jesús|||0000-0001-5421-8513
Arda, Ana
Delgado, Rafael
Bernardi, Anna
Fieschi, Franck
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
description DC-SIGN (CD209) and L-SIGN (CD209L) are two C-type lectin receptors (CLRs) that facilitate SARS-CoV-2 infections as viral co-receptors. SARS-CoV-2 manipulates both DC-SIGN and L-SIGN for enhanced infection, leading to interest in developing receptor antagonists. Despite their structural similarity (82% sequence identity), they function differently. DC-SIGN, found in dendritic cells, shapes the immune response by recognizing pathogen-associated carbohydrate patterns. In contrast, L-SIGN, expressed in airway epithelial endothelial cells, is not directly involved in immunity. COVID-19's primary threat is the hyperactivation of the immune system, potentially reinforced if DC-SIGN engages with exogenous ligands. Therefore, L-SIGN, co-localized with ACE2-expressing cells in the respiratory tract, is a more suitable target for anti-adhesion therapy. However, designing a selective ligand for L-SIGN is challenging due to the high sequence identity of the Carbohydrate Recognition Domains (CRDs) of the two lectins. We here present Man84, a mannose ring modified with a methylene guanidine triazole at position 2. It binds L-SIGN with a KD of 12.7μM ± 1 μM (ITC) and is the first known L-SIGN selective ligand, showing 50-fold selectivity over DC-SIGN (SPR). The X-ray structure of the L-SIGN CRD/Man84 complex reveals the guanidinium group's role in achieving steric and electrostatic complementarity with L-SIGN. This allows us to trace the source of selectivity to a single amino acid difference between the two CRDs. NMR analysis confirms the binding mode in solution, highlighting Man84's conformational selection upon complex formation. Dimeric versions of Man84 achieve additional selectivity and avidity in the low nanomolar range. These compounds selectively inhibit L-SIGN dependent trans-infection by SARS-CoV-2 and Ebola virus. Man84 and its dimeric constructs display the best affinity and avidity reported to date for low-valency glycomimetics targeting CLRs. They are promising tools for competing with SARS-CoV-2 anchoring in the respiratory tract and have potential for other medical applications.
publishDate 2024
dc.date.none.fl_str_mv 2
2024-01-01
2024
2024-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/321730
https://dx.doi.org/urn:doi:10.1039/d4sc02980a
url https://ddd.uab.cat/record/321730
https://dx.doi.org/urn:doi:10.1039/d4sc02980a
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CB21/13/00039
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 FIS/PI21/00989
European Commission https://doi.org/10.13039/501100000780 101137157
European Commission https://doi.org/10.13039/501100000780 101145709
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 CEX2021-001136-S
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
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