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Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2.
Cramer, Jonathan; Lakkaichi, Adem; Aliu, Butrint; Jakob, Roman P; Klein, Sebastian; Cattaneo, Ivan; Jiang, Xiaohua; Rabbani, Said; Schwardt, Oliver; Zimmer, Gert; Ciancaglini, Matias; Abreu Mota, Tiago; Maier, Timm; Ernst, Beat.
  • Cramer J; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Lakkaichi A; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University of Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany.
  • Aliu B; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Jakob RP; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Klein S; Department Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
  • Cattaneo I; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Jiang X; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Rabbani S; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Schwardt O; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Zimmer G; University of Basel, Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Ciancaglini M; Institute of Virology and Immunology, Sensemattstrasse 293, 3147 Mittelhäusern, Switzerland.
  • Abreu Mota T; Department Biomedicine, University of Basel, Petersplatz 8, 4051 Basel, Switzerland.
  • Maier T; Department Biomedicine, University of Basel, Petersplatz 8, 4051 Basel, Switzerland.
  • Ernst B; Department Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
J Am Chem Soc ; 143(42): 17465-17478, 2021 10 27.
Article in English | MEDLINE | ID: covidwho-1469951
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 trans-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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cell Adhesion Molecules / Receptors, Cell Surface / Lectins, C-Type / COVID-19 Drug Treatment Limits: Humans Language: English Journal: J Am Chem Soc Year: 2021 Document Type: Article Affiliation country: Jacs.1c06778

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cell Adhesion Molecules / Receptors, Cell Surface / Lectins, C-Type / COVID-19 Drug Treatment Limits: Humans Language: English Journal: J Am Chem Soc Year: 2021 Document Type: Article Affiliation country: Jacs.1c06778