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.
J Med Chem
; 64(19): 14332-14343, 2021 10 14.
Article
in English
| MEDLINE | ID: covidwho-1621195
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Phenols
/
Viral Proteins
/
Glycoconjugates
/
Glycoproteins
/
Cell Adhesion Molecules
/
Receptors, Cell Surface
/
Lectins, C-Type
/
Calixarenes
/
Hydroxamic Acids
Type of study:
Experimental Studies
/
Randomized controlled trials
Limits:
Humans
Language:
English
Journal:
J Med Chem
Journal subject:
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Acs.jmedchem.1c00818
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