ICP seminar: Controlling the impact of C-type lectin receptors in viral infections and immunity: roles of DC/L-SIGN in SARS-CoV2 trans infection and development of selective glycomimetic antagonists.

08 December 2023 par clavaguera
Pr. Franck Fieschi, Univ. of Grenoble Alpes, Institut de Biologie Structurale - Thursday, December 21 2023

9:30 am in Magat Room, building 349

Key word: Immunity, Host-Pathogens interaction, SARS-COV-2, glycoscience, Drug-Design, glycomimetic developments, Multivalency, Affinity vs Avidity

 

C-type lectin receptors (CLRs) are a large family of Pattern Recognition Receptors, dedicated to the detection of carbohydrate-based motifs, using a Ca2+ ion for recognition. Innate immune cells express a variety of CLRs, which shape the immune response, often in cross-talk with Toll Like Receptors. Some pathogens have found strategies to circumvent CLR’s role or even to use them in their infection process. This is the case of several deadly viruses, like HIV. Subversion of several CLRs has been reported, including MGL, L-SIGN and especially DC-SIGN, which is the most widely reported co-receptors facilitating viral infection. During the past 15 years, my group was engaged, in the context of a strong collaboration with the group of A. Bernardi in Milano, to develop glycomimetic ligands able to interfere with DC-SIGN recognition, thus inhibiting its role in viral infections. It took also new directions with the pandemic event of 2020. I will described how we have demonstrated the involvement of CLRs in some dissemination process of the SARS-CoV-2 virus.1–3 This long term project, over the last 18 years, took us from the design of glycomimetic able to mimic the monovalent oligosaccharide ligands of DC-SIGN4, to the refinement of their activity by structural optimization5 and of their multivalent presentation6. Biophysical methods were devised, optimized to produce structure-activity-relationship for the designed mimics and to account for the dynamic and the different topology of the receptors presentation7,8. Structures from crystallographic studies were used in the design to increase the affinity and selectivity of ligands for a specific lectin. In the process, we have developed general principles for the selective design of potent glycomimetic ligands for CLRs and tools for their study.

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  8. Porkolab, V. et al. ACS Cent. Sci. 9, 709–718 (2023).