Increasing the Chemical Space of L-SIGN Specific Glycomimetics
Year: 2025
Type: article
Abstract: Selective ligands for the C-type lectin receptor L-SIGN offer promising avenues in antiviral therapies and for tissue-specific delivery. We recently reported that a guanidine-bearing modified mannose glycomimetic, called Man84, binds to L-SIGN with micromolar affinity and high-selectivity against the homologue lectin DC-SIGN. Here we describe a series of Man84 isosteres (ligands 2–11) that maintain or improve on this selectivity. The affinity of the ligands for L-SIGN, as well as their selectivity against DC-SIGN, were evaluated by Surface Plasmon Resonance inhibition assays using immobilized SARS-CoV-2 Spike protein. Compounds 4, 5 and 9 were found to bind to L-SIGN with low micromolar affinity and 50–94-fold selectivity, thus matching or exceeding the performance of Man84. The crystal structure of the L-SIGN CRD/4 complex was solved and highlighted the critical role of a bidentate H-bond interaction of the ligands with the side chain of E370 in L-SIGN.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Università degli Studi di Milano, Agence Nationale de la Recherche, Papua New Guinea University of Technology, Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche, Centre National de la Recherche Scientifique, French Infrastructure for Integrated Structural Biology, Ministero dell'Università e della Ricerca, NextGenerationEU
OpenAlex ID: W4415313846