7NL7

Crystal Structure of DC-SIGN in complex with a triazole-based glycomimetic ligand

7NL7 の概要

• エントリーDOI: 10.2210/pdb7nl7/pdb
• 分子名称: DC-SIGN, CRD domain, CALCIUM ION, 3-Aminopropyl 2-deoxy-2-(4-phenyl-1,2,3-triazol-1-yl)-alpha-D-mannopyranoside, ... (4 entities in total)
• 機能のキーワード: lectin, sugar binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18644.68

構造登録者

Jakob, R.P.,Cramer, J.,Lakkaichi, A.,Aliu, B.,Cattaneo, I.,Klein, S.,Jiang, X.,Rabbani, S.,Schwardt, O.,Ernst, B.,Maier, T. (登録日: 2021-02-22, 公開日: 2021-10-27, 最終更新日: 2024-10-16)

主引用文献

Cramer, J.,Lakkaichi, A.,Aliu, B.,Jakob, R.P.,Klein, S.,Cattaneo, I.,Jiang, X.,Rabbani, S.,Schwardt, O.,Zimmer, G.,Ciancaglini, M.,Abreu Mota, T.,Maier, T.,Ernst, B.
Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2.
J.Am.Chem.Soc., 143:17465-17478, 2021

PubMed Abstract: The C-type lectin receptor DC-SIGN is a pattern recognition receptor expressed on macrophages and dendritic cells. It has been identified as a promiscuous entry receptor for many pathogens, including epidemic and pandemic viruses such as SARS-CoV-2, Ebola virus, and HIV-1. In the context of the recent SARS-CoV-2 pandemic, DC-SIGN-mediated virus dissemination and stimulation of innate immune responses has been implicated as a potential factor in the development of severe COVID-19. Inhibition of virus binding to DC-SIGN, thus, represents an attractive host-directed strategy to attenuate overshooting innate immune responses and prevent the progression of the disease. In this study, we report on the discovery of a new class of potent glycomimetic DC-SIGN antagonists from a focused library of triazole-based mannose analogues. Structure-based optimization of an initial screening hit yielded a glycomimetic ligand with a more than 100-fold improved binding affinity compared to methyl α-d-mannopyranoside. Analysis of binding thermodynamics revealed an enthalpy-driven improvement of binding affinity that was enabled by hydrophobic interactions with a loop region adjacent to the binding site and displacement of a conserved water molecule. The identified ligand was employed for the synthesis of multivalent glycopolymers that were able to inhibit SARS-CoV-2 spike glycoprotein binding to DC-SIGN-expressing cells, as well as DC-SIGN-mediated -infection of ACE2 cells by SARS-CoV-2 spike protein-expressing viruses, in nanomolar concentrations. The identified glycomimetic ligands reported here open promising perspectives for the development of highly potent and fully selective DC-SIGN-targeted therapeutics for a broad spectrum of viral infections.

PubMed: 34652144
DOI: 10.1021/jacs.1c06778

実験手法

X-RAY DIFFRACTION (2.1 Å)