Abstract
In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antiviral Agents / chemistry
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Antiviral Agents / metabolism
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Antiviral Agents / pharmacology
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Calixarenes / chemistry*
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Cell Adhesion Molecules / antagonists & inhibitors*
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Cell Adhesion Molecules / metabolism
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Cell Line
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Cytomegalovirus / metabolism
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Dendritic Cells / cytology
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Dendritic Cells / metabolism
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Ebolavirus / physiology
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Glycoconjugates / chemistry
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Glycoconjugates / metabolism*
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Glycoconjugates / pharmacology
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Glycoproteins / antagonists & inhibitors*
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Humans
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Hydroxamic Acids / chemistry*
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Jurkat Cells
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Lectins, C-Type / antagonists & inhibitors*
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Lectins, C-Type / metabolism
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Models, Biological
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Phenols / chemistry*
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Protein Binding
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Receptors, Cell Surface / antagonists & inhibitors*
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Receptors, Cell Surface / metabolism
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / isolation & purification
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Viral Proteins / antagonists & inhibitors*
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Viral Proteins / genetics
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Viral Proteins / metabolism
Substances
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Antiviral Agents
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Cell Adhesion Molecules
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DC-specific ICAM-3 grabbing nonintegrin
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Glycoconjugates
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Glycoproteins
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Hydroxamic Acids
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Lectins, C-Type
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Phenols
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Receptors, Cell Surface
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Recombinant Proteins
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Viral Proteins
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calix(4)arene
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Calixarenes