Synthetic Siglec-9 Agonists Inhibit Neutrophil Activation Associated with COVID-19.

Severe cases of coronavirus disease 2019 (COVID-19), caused by infection with SARS-Cov-2, are characterized by a hyperinflammatory immune response that leads to numerous complications. Production of proinflammatory neutrophil extracellular traps (NETs) has been suggested to be a key factor in inducing a hyperinflammatory signaling cascade, allegedly causing both pulmonary tissue damage and peripheral inflammation. Accordingly, therapeutic blockage of neutrophil activation and NETosis, the cell death pathway accompanying NET formation, could limit respiratory damage and death from severe COVID-19. Here, we demonstrate that synthetic glycopolymers that activate the neutrophil checkpoint receptor Siglec-9 suppress NETosis induced by agonists of viral toll-like receptors (TLRs) and plasma from patients with severe COVID-19. Thus, Siglec-9 agonism is a promising therapeutic strategy to curb neutrophilic hyperinflammation in COVID-19.
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Competing Interests: C.S.D. and C.R.B. are coinventors on a patent application for cis-binding Siglec agonist glycopolymers as immune suppressants (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 Bio, and a member of the Board of Directors of Eli Lily & Company. C.A.B. is a Scientific Advisory Board member of Catamaran Bio.