Modulation of Immune Cell Reactivity with Cis-Binding Siglec Agonist

Primary inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach to for anti-inflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in cis, leading to inhibitory signaling. Specifically, we construct a cis-binding agonist of Siglec-9 and show that it modulates MAPK signaling in reporter cell lines, immortalized macrophage and microglial cell lines, and primary human macrophages. These cis-binding agonists of Siglecs present a new modality for therapeutic suppression of immune cell reactivity.