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

Abstract

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 (α‐ d‐Man‐(1→2)‐α‐ d‐Man, α‐ d‐Man‐(1→2)‐α‐ d‐Man‐(1→2)‐α‐ d‐Man‐(1→3)‐α‐ d‐Man) and branched (α‐ d‐Man‐(1→6)‐[α‐ d‐Man‐(1→3)]‐α‐ d‐Man) oligomannosides, as well as α‐ 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.