Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19, 2023, Geyer et al

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19

Abstract
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.


https://www.life-science-alliance.org/content/6/11/e202302106

 

Tweet by den Dunnen on this study and possible connection to LC www.twitter.com/DrDenDunnen/status/1701883106905493862 translated into English: “This is indeed specific drug candidate for severe acute COVID-19, which is very likely to have a different cause than Long-COVID. So this is not a candidate drug for Long COVID. However, we are now investigating involvement of (auto)antibodies in endothelial function in LC.”