![Author ORCID: We display the ORCID iD icon alongside authors names on our website to acknowledge that the ORCiD has been authenticated when entered by the user. To view the users ORCiD record click the icon. [opens in a new tab]](https://chemrxiv.org/engage/assets/public/chemrxiv/images/logos/orcid.png)
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 homolog 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 bifurcated H-bond interaction of the ligands with the side chain of E370 in L-SIGN.
Supplementary materials
Title
Supporting Information
Description
SI includes: sensorgrams and inhibition curves of SPR binding competition assays of DC-SIGN and L-SIGN; correlation graphs for L-SIGN affinity and selectivity; crystallographic data and statistics of L-SIGN CRD/4 complex; details of the computational (docking) studies; NMR spectral data of compounds 2-21, Molecular Formula Strings (cvs). Primary data can be found in supporting information or can be requested to the authors.
Actions
