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Modulation of immune cell reactivity with cis-binding Siglec-9 agonists

ABSTRACT: Primary inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, ranging from chronic pain to permanent blindness. Siglec-9 is an immunoinhibitory receptor expressed on many types of phagocytes and is a promising target for anti-inflammatory therapeutics. We developed a lipid-tethered glycopolypeptide that spontaneously inserts into cell membranes and specifically binds Siglec-9 in cis on the surface of cells. We demonstrate that when inserted in a cell membrane and cis-binding, but not as a soluble trans-binding agent, this glycopolypeptide and agonizes Siglec-9, inhibiting inflammatory activity in reporter systems, phagocytic cell lines, and primary human macrophages. Thus, membrane-tethered cis-agonists of Siglec-9 are a new modality for therapeutic suppression of immune cell reactivity.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Macrophage

SUBMITTER: Nicholas Riley

LAB HEAD: Carolyn Bertozzi

PROVIDER: PXD018774 | Pride | 2021-01-14

REPOSITORIES: Pride

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Modulation of immune cell reactivity with <i>cis</i>-binding Siglec agonists.

Delaveris Corleone S CS Chiu Shannon H SH Riley Nicholas M NM Bertozzi Carolyn R CR

Proceedings of the National Academy of Sciences of the United States of America 20210101 3

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 for antiinflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in <i>cis</i>, leading to i ...[more]

PMID: 33431669

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			Action	DRS
	2019_11_11_LPS_FT_1.raw	Raw
	2019_11_11_LPS_FT_2.raw	Raw
	2019_11_11_LPS_FT_3.raw	Raw
	2019_11_11_LPS_Phos_1.raw	Raw
	2019_11_11_LPS_Phos_2.raw	Raw