Combating DC-SIGN-mediated SARS-CoV-2 dissemination by glycan-mimicking polymers

Many viruses exploit the human C-type lectin receptor dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) for cell entry and virus dissemination. An inhibition of DC-SIGN-mediated virus attachment by glycan-derived ligands has, thus, emerged as a promising strategy toward broad-spectrum antiviral therapeutics. In this contribution, several cognate fragments of oligomannose- and complex-type glycans grafted onto a poly-l-lysine scaffold are evaluated as polyvalent DC-SIGN ligands. The range of selected carbohydrate epitopes encompasses linear (alpha- d-Man-(1 -> 2)-alpha- d-Man, alpha- d-Man-(1 -> 2)-alpha- d-Man-(1 -> 2)-alpha- d-Man-(1 -> 3)-alpha- d-Man) and branched (alpha- d-Man-(1 -> 6)-[alpha- d-Man-(1 -> 3)]-alpha- d-Man) oligomannosides, as well as alpha- l-Fuc. The thermodynamics of binding are investigated on a mono- and multivalent level to shed light on the molecular details of the interactions with the tetravalent receptor. Cellular models of virus attachment and DC-SIGN-mediated virus dissemination reveal a high potency of the presented glycopolymers in the low pico- and nanomolar ranges, respectively. The high activity of oligomannose epitopes in combination with the biocompatible properties of the poly- l-lysine scaffold highlights the potential for further preclinical development of polyvalent DC-SIGN ligands.