Reference Database

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.
Geyer, Chiara E
Chen, Hung-Jen
Bye, Alexander P
Manz, Xue D
Guerra, Denise
Caniels, Tom G
Bijl, Tom Pl
Griffith, Guillermo R
Hoepel, Willianne
de Taeye, Steven W
Veth, Jennifer
Vlaar, Alexander Pj
Amsterdam UMC COVID-19 Biobank
Vidarsson, Gestur
Bogaard, Harm Jan
Aman, Jurjan
Gibbins, Jonathan M
van Gils, Marit J
de Winther, Menno Pj
den Dunnen, Jeroen
Life Sci Alliance 2023 Nov;6(11): e202302106

Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.

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