SELECTIVE GLYCOMIMETIC LIGANDS OF C-TYPE LECTIN RECEPTORS

C-type lectin receptors (CLRs) are calcium-dependent proteins dedicated to sensing glycan motifs, including those expressed on the surface of invading pathogens. Although this recognition event usually leads to induction of an immune response, many pathogens have evolved mechanisms to exploit lectins to promote infection. A number of viruses of major impact on public health, such as HIV-1, Ebola and SARS-CoV-2, adopt this strategy to subvert host defence responses and enhance the infectious process. Selective inhibitors of lectins have thus high potential as therapeutic agents, but their use is limited by the intrinsic low affinity and selectivity of carbohydrate-based molecules towards CLRs. These limitations can generally be overcome through the use of chemically modified analogues of sugars that emulate carbohydrate activities but presents improved drug-like properties. In this thesis we disclose a glycomimetic approach to selectively target the C-type lectin DC-SIGN and its homologue L-SIGN, which are involved in the recognition of several viruses (e.g. HIV-1, Ebola, Dengue, SARS-CoV-2). A library of monovalent mannose-based glycomimetic ligands has been synthetized by varying the nature and the position of the functionalization. Ligand affinity towards target lectin receptors has been evaluated through SPR (Surface Plasmon Resonance) competition assays, performed in the group of Prof. Fieschi in Grenoble (IBS). The most promising ligands were then selected for construction of multivalent glycoconjugates, to further increase ligand affinity and selectivity. Multivalent constructs were built on different platforms and the synthetized ligands were evaluated as DC/L-SIGN antagonists via SPR direct interaction assays. The determination of their antiviral activity in cellular studies is currently ongoing in the group of Dr. Delgado (Hospital Universitario 12 de Octubre, Madrid).