Topological and Multivalent Effects in Glycofullerene Oligomers as EBOLA Virus Inhibitors

Abstract

The synthesis of new biocompatible antiviral materials to fight against the development of multidrug resistance is being widely explored. Due to their unique globular structure and excellent properties, [60]fullerene-based antivirals are very promising bioconjugates. In this work, fullerene derivatives with different topologies and number of glycofullerene units were synthesized by using a SPAAC copper free strategy. This procedure allowed the synthesis of compounds 1-3, containing from 20 to 40 mannose units, in a very efficient manner and in short reaction times under MW irradiation. The glycoderivatives were studied in an infection assay by a pseudotyped viral particle with Ebola virus GP1. The results obtained show that these glycofullerene oligomers are efficient inhibitors of EBOV infection with IC50s in the nanomolar range. In particular, compound 3, with four glycofullerene moieties, presents an outstanding relative inhibitory potency (RIP). We propose that this high RIP value stems from the appropriate topological features that efficiently interact with DC-SIGN.

Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

“…It is thought that such flexibility is at the root of DC-SIGN capabilities to recognize and adapt to a wide repertoire of pathogen glycans whereas other lectin receptors, with fixed site spacing, recognize limited molecular patterns. Strikingly, this flexibility, and thus inter-CRDs distances variability, is rarely taken into consideration within the plethora of work aiming at designing multivalent ligand targeting DC-SIGN. − In order to evaluate its impacts on the observed avidity boost, the conformations attained during 2 μs of explicit-solvent molecular dynamics (MD) simulation of the DC-SIGN tetramer/neck model are shown in Figure (see also in Supporting Information Movies S1 and S2).…”

Multivalent glycosystems for human lectins

“…In brief, our group and Martı ´n's group reported a straightforward strategy based on click reactions (both CuAAC and SPAAC) [132][133][134] to efficiently attach twelve carbohydrate or glycodendron residues simultaneously to alkyne-or cyclooctynesubstituted C 60 hexakis-adducts in few steps 135 or to achieve the preparation of simple glycofullerene oligomers. 136 In order to dramatically increase the valency and the size of these systems, both tridecafullerene superballs 137 bearing 120 peripheral mannose or galactose (as negative control) ligands and nanoballs 91 grafted with up to 360 a(1,2)mannobioside units, 138 increased by 3-4 fold the antiviral activity in comparison with the corresponding mannosylated compounds. 30,139,140 It is important to highlight that the giant globular multivalent glycofullerene with 360 sugar units represents the fastest dendrimeric growth reported to date.…”

“…Using pseudotyped Ebola viral particles as infectious agents, glycofullerene, glycodendrofullerene and oligomers coated with mannose residues were able to inhibit the infection of DC-SIGN Jurkat cells with IC 50 s from 2000 for the simplest compound to 32 nM for the oligomers with higher number of sugars (40 mannose units), whereas the tridecafullerene superball bearing 120 pheripheral mannose showed an IC 50 of 0.7 nM. [135][136][137] Regarding nanoballs grafted with a(1,2)mannobioside units, the nanoball bearing 360 disaccharides was able to inhibit the viral infection of both Zika and Dengue viruses with an IC 50 in the picomolar range (IC 50 of 67 pM for ZIKV and IC 50 of 35 pM for DENV). 91 Moreover, glyconanomaterials constituted by a mannose glycofullerene or a nonavalent glycodendron attached to SWCNT (single-walled carbon nanotube), MWCNT (multiwalled carbon nanotube) and SWCNH (single-walled carbon nanohorn) carbon nanoforms were prepared.…”

Carbon-based glyco-nanoplatforms: towards the next generation of glycan-based multivalent probes

“…10 ). 161 The ability of these oligomers to inhibit the infection of DC-SIGN Jurkat cells using pseudotyped Ebola viral particles as infectious agents were thus measured. It is important to highlight that all these glyconanostructures were not cytotoxic to cell lines at the concentrations used in the infection experiments, allowing their study of their potential to inhibit the viral infection.…”