DC-SIGN (CD209) and L-SIGN (CD209L) are two C-type lectin receptors (CLRs) structurally homologous, but functionally rather different. DC-SIGN, expressed by dendritic cells and dedicated to recognizing carbohydrate molecular patterns associated to pathogens, contributes to shaping the immune response; L-SIGN is notably expressed in endothelial cells from airway epithelia and is not directly involved in immunity. Some viruses are able to manipulate CLRs during their infection. Indeed, SARS-CoV-2 utilizes both DC-SIGN and L-SIGN for enhanced infection through a transinfection mechanism, sparking interest in the development of antagonists for these receptors. COVID-19’s major threat is associated to hyperactivation of the immune system that might be reinforced if DC-SIGN is engaged by exogenous ligands. Thus L‐SIGN, co-localized with ACE2‐ expressing cells in the respiratory tract, appears as a more appropriate target for anti-adhesion therapy. However, the Carbohydrate Recognition Domains (CRDs) of the two lectins share 72% sequence identity, making the creation of a selective ligand for L-SIGN a real challenge. We introduce here Man84, a mannose ring modified at position 2 with a methylene guanidine triazole, which binds L-SIGN with a KD of 12.7 μM ± 1 μM (ITC) and represents the first known L-SIGN selective ligand, showing a 50-fold selectivity over DC-SIGN (SPR). The X-ray structure of the L-SIGN CRD/Man84 complex reveals the role of the guanidinium group, which attains steric and electrostatic complementarity with L-SIGN, and allows to pinpoint the source of selectivity to a single amino acid difference between the two CRDs. NMR analysis confirms the binding mode in solution, highlighting a conformational selection of Man84 upon complex formation. Additional selectivity and avidity in the low nanomolar range have been reached with dimeric versions of Man84. These compounds selectively inhibit L-SIGN dependent trans infection by SARS-CoV-2 and by Ebola virus. Man84 and its dimeric constructs display the best affinity and avidity reported to date for low-valency glycomimetics targeting a CLRs. Their performance makes them viable tools for competing with SARS-CoV-2 anchoring in the respiratory tract and their potential extends to additional applications in other medical contexts.
Development of a highly selective glycomimetic ligand for L-SIGN: a new tool against SARS-CoV-2 and Ebola viruses / C. Delaunay, S. Pollastri, M. Thépaut, G. Cavazzoli, L. Belvisi, C. Bouchikri, N. Labiod, A. Gimeno, A. Franconetti, J. Jiménez-Barbero, A. Ardá, R. Delgado, A. Bernardi, F. Fieschi. - (2023 Dec 20). [10.26434/chemrxiv-2023-tf1fg]
Development of a highly selective glycomimetic ligand for L-SIGN: a new tool against SARS-CoV-2 and Ebola viruses
S. PollastriCo-primo
;G. Cavazzoli;L. Belvisi;A. Bernardi
;
2023
Abstract
DC-SIGN (CD209) and L-SIGN (CD209L) are two C-type lectin receptors (CLRs) structurally homologous, but functionally rather different. DC-SIGN, expressed by dendritic cells and dedicated to recognizing carbohydrate molecular patterns associated to pathogens, contributes to shaping the immune response; L-SIGN is notably expressed in endothelial cells from airway epithelia and is not directly involved in immunity. Some viruses are able to manipulate CLRs during their infection. Indeed, SARS-CoV-2 utilizes both DC-SIGN and L-SIGN for enhanced infection through a transinfection mechanism, sparking interest in the development of antagonists for these receptors. COVID-19’s major threat is associated to hyperactivation of the immune system that might be reinforced if DC-SIGN is engaged by exogenous ligands. Thus L‐SIGN, co-localized with ACE2‐ expressing cells in the respiratory tract, appears as a more appropriate target for anti-adhesion therapy. However, the Carbohydrate Recognition Domains (CRDs) of the two lectins share 72% sequence identity, making the creation of a selective ligand for L-SIGN a real challenge. We introduce here Man84, a mannose ring modified at position 2 with a methylene guanidine triazole, which binds L-SIGN with a KD of 12.7 μM ± 1 μM (ITC) and represents the first known L-SIGN selective ligand, showing a 50-fold selectivity over DC-SIGN (SPR). The X-ray structure of the L-SIGN CRD/Man84 complex reveals the role of the guanidinium group, which attains steric and electrostatic complementarity with L-SIGN, and allows to pinpoint the source of selectivity to a single amino acid difference between the two CRDs. NMR analysis confirms the binding mode in solution, highlighting a conformational selection of Man84 upon complex formation. Additional selectivity and avidity in the low nanomolar range have been reached with dimeric versions of Man84. These compounds selectively inhibit L-SIGN dependent trans infection by SARS-CoV-2 and by Ebola virus. Man84 and its dimeric constructs display the best affinity and avidity reported to date for low-valency glycomimetics targeting a CLRs. Their performance makes them viable tools for competing with SARS-CoV-2 anchoring in the respiratory tract and their potential extends to additional applications in other medical contexts.File | Dimensione | Formato | |
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