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

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 IC 50 inhibition of both DC-SIGNdependent 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.

Heteroglycoclusters through Unprecedented Orthogonal Chemistry Based on N‐Alkylation of N‐Acylhydrazone

“…[4]arene heteroglycoclustersbased NAH. The following example (Scheme 8) uses the cone p-t Bu-calix [4]arene phenolic template that we have previously used as a preorganized scaffold to design homomultivalent LecB [16] and DC-SIGN [15,67,68] lectin antagonists. The selective 1,3bis-O-alkylation of cone p t Bu-calix [4]arene at the lower rim leaving the two remaining OH groups free is a well-known transformation that usually takes place in the presence of alkylating reagent and K 2 CO 3 as a base.…”

“…The latter brings together α‐L‐fucose and α‐D‐galactose branching from an N ‐Alk‐NAH bearing linker. Tetra‐azido 1,3‐ alt p ‐ t Bu‐thiacalix[4]arene 36 [15] (Scheme 9a) was used as a key intermediate having previously been used for the synthesis of strong inhibitors of DC‐SIGN‐dependent viral infections [15,68] . Firstly we synthesized tetra‐ester 37 in 70 % yield from 36 by a click reaction with an excess of propiolic methyl ester.…”

“…Below, we have extended the strategy to the 1,3‐ alt p ‐ t Bu‐thiacalix[4]arene as a valuable scaffold previously used in homomultivalent glycoclusters [15,68] …”

“…Tetraazido 1,3-alt p-t Bu-thiacalix [4]arene 36 [15] (Scheme 9a) was used as a key intermediate having previously been used for the synthesis of strong inhibitors of DC-SIGN-dependent viral infections. [15,68] Firstly we synthesized tetra-ester 37 in 70 % yield from 36 by a click reaction with an excess of propiolic methyl ester. Reaction with an excess of hydrazine in refluxing ethanol gave the tetra-acylhydrazide 38 in 80 % yield.…”

“…Below, we have extended the strategy to the 1,3-alt p-t Buthiacalix [4]arene as a valuable scaffold previously used in homomultivalent glycoclusters. [15,68] Synthesis of the first 1,3-alt p-t Bu-thiacalix [4]arene heteroglycoclusters-based NAH. Besides heteroglyconjugates as mimics of blood and microbial antigens, [7,26,27] the known heteroglycoconjugate synthetic strategies have also targeted the association of different epitopes to synergistically inhibit multiple cognate lectins involved in the same infectious disease.…”