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Published on: October 28, 2019
Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus
S Brument1, C Cheneau, Y Brissonnet
1LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes cedex 3, France. sebastien.gouin@univ-nantes.fr.
New mannoside compounds block Human Cytomegalovirus (HCMV) infection by targeting the interaction between glycoprotein B (gB) and DC-SIGN. Multivalent mannosides, especially THM-coated dextran polymers, show potent anti-HCMV activity, offering a promising therapeutic strategy.
Area of Science:
- Virology
- Immunology
- Carbohydrate Chemistry
Background:
- Human cytomegalovirus (HCMV) is a prevalent beta-herpesvirus causing significant morbidity in newborns and immunocompromised individuals.
- HCMV utilizes its envelope glycoprotein B (gB) to interact with Dendritic Cell-Specific ICAM-3 Grabbing Non integrin (DC-SIGN) for host cell entry.
- Existing treatments for HCMV are limited, necessitating novel therapeutic approaches.
Purpose of the Study:
- To develop and evaluate novel DC-SIGN blockers as chemical anti-adhesives for HCMV.
- To investigate the efficacy of mono-, di-, tetra-, and polyvalent mannosides in inhibiting HCMV-DC-SIGN interactions.
- To assess the potential of these compounds in preventing DC-SIGN mediated HCMV infection of dendritic cells.
Main Methods:
- Synthesis of a series of mannoside derivatives, including mono-, di-, tetra-, and polyvalent structures.
- Design of multivalent mannosides to interact with DC-SIGN's carbohydrate recognition domains via chelation or bind-and-recapture mechanisms.
- Evaluation of the compounds' ability to block the gB-DC-SIGN interaction and prevent HCMV trans-infection of dendritic cells.
Main Results:
- Polymeric dextrans coated with triazolylheptylmannoside (THM) ligands demonstrated high potency, blocking gB-DC-SIGN interaction at nanomolar concentrations.
- A THM-coated dextran polymer (average 902 THM ligands) effectively blocked HCMV trans-infection with IC50 values in the picomolar range.
- Each THM moiety on the polymer was over 10,000 times more effective than the methylmannoside reference, with no observed cytotoxicity at 2 mM.
Conclusions:
- Multivalent mannosides, particularly THM-functionalized dextran polymers, represent the first reported chemical anti-adhesives against HCMV.
- These compounds effectively inhibit HCMV attachment to dendritic cells by blocking the gB-DC-SIGN interaction.
- The non-cytotoxic and highly potent nature of these THM-coated polymers makes them promising candidates for anti-HCMV therapies and potentially for other viruses utilizing DC-SIGN.
