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.
Subject(s)
Calixarenes/chemistry , Cell Adhesion Molecules/antagonists & inhibitors , Glycoconjugates/metabolism , Glycoproteins/antagonists & inhibitors , Hydroxamic Acids/chemistry , Lectins, C-Type/antagonists & inhibitors , Phenols/chemistry , Receptors, Cell Surface/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Cell Adhesion Molecules/metabolism , Cell Line , Cytomegalovirus/metabolism , Dendritic Cells/cytology , Dendritic Cells/metabolism , Ebolavirus/physiology , Glycoconjugates/chemistry , Glycoconjugates/pharmacology , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Jurkat Cells , Lectins, C-Type/metabolism , Models, Biological , Protein Binding , Receptors, Cell Surface/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Viral Proteins/genetics , Viral Proteins/metabolismABSTRACT
The aim of this review is to highlight how, in a syngeneic system, human mononuclear phagocytes respond to environments containing human adenovirus (HAdV) and soluble extracellular proteins that influence their innate immune response. Soluble extracellular proteins, including immunoglobulins, blood clotting factors, proteins of the complement system, and/or antimicrobial peptides (AMPs) can exert direct effects by binding to a virus capsid that modifies interactions with pattern recognition receptors and downstream signaling. In addition, the presence, generation, or secretion of extracellular proteins can indirectly influence the response to HAdVs via the activation and recruitment of cells at the site of infection.