Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN

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.