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20200630 Siglec Cis Agonists.pdf (4.35 MB)

Modulation of Immune Cell Reactivity with Cis-Binding Siglec Agonist

preprint
submitted on 02.07.2020 and posted on 03.07.2020 by Corleone Delaveris, Shannon Chiu, Nicholas Riley, Carolyn Bertozzi
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.

History

Email Address of Submitting Author

delaveri@stanford.edu

Institution

Stanford University

Country

United State

ORCID For Submitting Author

0000-0002-7291-2338

Declaration of Conflict of Interest

C.S.D. and C.R.B. are coinventors on a patent application related to this work (USPTO63046140). C.R.B. is a co-founder and Scientific Advisory Board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), and InterVenn Biosciences, and a member of the Board of Directors of Eli Lilly & Company.

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