Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.
Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.
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DOI：
10.26508/lsa.202302106
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发表时间：
2023-11
影响因子：
4.4
通讯作者：
den Dunnen, Jeroen
中科院分区：
文献类型：
--
作者：
Geyer, Chiara E.;Chen, Hung-Jen;Bye, Alexander P.;Manz, Xue;Guerra, Denise;Caniels, Tom G.;Bijl, Tom P. L.;Griffith, Guillermo R.;Hoepel, Willianne;de Taeye, Steven W.;Veth, Jennifer;Vlaar, Alexander P. J.;Vidarsson, Gestur;Bogaard, Harm Jan;Aman, Jurjan;Gibbins, Jonathan M.;van Gils, Marit J.;de Winther, Menno P. J.;den Dunnen, Jeroen
新冠肺炎仍然是一个主要的健康威胁，全球范围内的住院和死亡仍在持续。异常的抗体反应是严重新冠肺炎发生的一个重要原因，它通过引起炎症、水肿和血栓形成。在这里，我们确定恩托普替尼是治疗重症新冠肺炎的有前途的候选药物。此前，我们和其他人已经证明，SARS-CoV-2刺激性免疫球蛋白抗体通过触发巨噬细胞过度激活、破坏内皮屏障完整性和诱导血栓形成，在新冠肺炎的疾病严重程度中发挥主要作用。这种过度炎症依赖于高水平的Fc尾部糖基化抗体，导致Fcγ受体的过度激活。对于免疫调节疗法的发展，药物特异性是至关重要的，以抵消过度炎症，同时最大限度地减少对抗病毒免疫的抑制。我们在这里开发了一种体外激活试验来筛选特异性地对抗抗体诱导的病理的小分子药物。我们发现，针对SYK和PI3K的小分子抑制剂可以特异性地阻断抗棘波诱导的炎症。我们确定SYK抑制剂entospletinib是最有希望的候选药物，它还可以对抗抗尖峰电流引起的内皮功能障碍和血栓形成。此外，恩托普替尼还能抑制不同SARS-CoV-2变种引起的炎症反应。综合起来，这些数据表明恩托普替尼是一种有希望治疗严重新冠肺炎的药物。
COVID-19 still poses a major health threat with worldwide ongoing hospitalizations and mortality. Aberrant antibody responses are a crucial cause of development of severe COVID-19 by inducing hyperinflammation, edema, and thrombus formation. Here, we identified entospletinib as a promising therapeutic candidate against severe COVID-19. 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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DOI：
10.1056/nejmoa2119451
发表时间：
2022-04-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Andrews N;Stowe J;Kirsebom F;Toffa S;Rickeard T;Gallagher E;Gower C;Kall M;Groves N;O'Connell AM;Simons D;Blomquist PB;Zaidi A;Nash S;Iwani Binti Abdul Aziz N;Thelwall S;Dabrera G;Myers R;Amirthalingam G;Gharbia S;Barrett JC;Elson R;Ladhani SN;Ferguson N;Zambon M;Campbell CNJ;Brown K;Hopkins S;Chand M;Ramsay M;Lopez Bernal J
通讯作者：
Lopez Bernal J
DOI：
10.1007/s42399-020-00521-8
发表时间：
2020
期刊：
SN comprehensive clinical medicine
影响因子：
--
作者：
Bhattacharjee S;Banerjee M
通讯作者：
Banerjee M
影响因子：
7.3
作者：
Currie, Kevin S.;Kropf, Jeffrey E.;Mitchell, Scott A.
通讯作者：
Mitchell, Scott A.
Syk介导的PI3KDELTA转移到前缘控制的层状叶片和白细胞的迁移。
影响因子：
3.7
作者：
Schymeinsky, Juergen;Then, Cornelia;Sindrilaru, Anca;Gerstl, Ronald;Jakus, Zoltan;Tybulewicz, Victor L. J.;Scharffetter-Kochanek, Karin;Walzog, Barbara
通讯作者：
Walzog, Barbara
DOI：
10.1084/jem.186.7.1027
发表时间：
1997-10-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Crowley MT;Costello PS;Fitzer-Attas CJ;Turner M;Meng F;Lowell C;Tybulewicz VL;DeFranco AL
通讯作者：
DeFranco AL