Sialyl Lewisx Glycomimetics as E- and P-Selectin Antagonists Targeting Hyperinflammation

Abstract

Inflammatory disorders, such as sepsis, pancreatitis, and severe COVID-19, often cause immune dysfunction and high mortality. These conditions trigger excessive immune cell influx, leading to cytokine storms, organ damage, and compensatory immune suppression that results in immunoparalysis, organ dysfunction, and reinfection. Controlled and reversible immunosuppression limiting immune cell recruitment to inflammation sites could reduce hyperinflammation and prevent immune exhaustion. PSGL-1 on leukocytes binds to vascular P- and E-selectins via its sialyl Lewis^x pharmacophore, triggering key features of systemic inflammatory response syndrome and sepsis. We report the discovery of two immunomodulators, sialyl Lewis^x glycomimetics (12 and 13), with a tetrazole carboxyl bioisostere of 3a, which binds P- and E-selectin and blocks their interaction with PSGL-1. In an in vivo hyperinflammation model, they reduced immune cell recruitment, evidenced by decreased neutrophils, CD11b+, monocytes/macrophages, and PSGL-1-positive cells at various time points. These glycomimetics may be promising leads for managing the systemic inflammatory response syndrome.