E-selectin/ligand interdiction for inflammation in the ARDS symptoms in COVID19
E-selectin is a key to the first step in inflammation where E-selectin ligand Sialyl LeX binds E-selectin on capillary endothelium for neutrophil extravasation. Mulligan et al. (1993) early showed in a mouse lung inflammation model of ARDS that oligosaccharides containing Sialyl LeX inhibited neutrophils from causing the pneumonic symptoms. Glycomimetics, Inc., under John Magnani’s scientific direction, has developed pan-selectin inhibitors and follow-on compounds that may also be effective in interdiction of the ARDS pathology (Chang et al. 2010). Magnani et al. developed a potent anti-inflammatory Sialyl LeX analog that interdicted inflammation in sickle cell anemia (Chang et al. 2010), and this and follow-on compounds from glycomimetics could be employed to test COVID19 lung and cardiac inflammation. Neelamegham, Matta et al. (Wang et al. 2018) reported using thioglycoside N-glycosylation decoys to hijack E-selectin ligand glycosylation, such that neutrophils treated with acetylated GlcNAc-S-NAP are 90% inhibited in rolling and tethering, and 90% inhibited in extravasation in a mouse ex-vivo model. Experiments with lung inflammation mouse models such as used by Mulligan et al. (1993) should be pursued toward finding drugs for the deadly pneumonic phase of COVID19 that is responsible for most fatalities.
It seems a reasonable approach that interfering with host glycosylation systems hijacked by SARS COV2, plus interfering with the ACE2 receptor glycosylation may combine to 1) interdict infectivity and 2) glycosylation interference with Sialyl LeX can inhibit E-selectin-based inflammatory responses, mitigating the Covid19 ARDS pathology. Important here is that decoys of glycosylation address the host enzyme systems; therefore, the virus cannot perform a simple mutation to overcome the interdiction, as in vaccines, like influenza. In addition, several of the compounds are FDA approved for other indications, which could be repurposed and tested off-label.