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Παρασκευή 15 Ιουνίου 2018

Identification of complement inhibitory activities of two chemotherapeutic agents using a high-throughput cell imaging-based screening assay

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Publication date: September 2018
Source:Molecular Immunology, Volume 101
Author(s): Lingjun Zhang, Yuriy Fedorov, Drew Adams, Feng Lin
Excessive complement activation contributes significantly to the pathogeneses of various diseases. Currently, significant developmental research efforts aim to identify complement inhibitors with therapeutic uses have led to the approval of one inhibitor for clinical use. However, most existing complement inhibitors are based on monoclonal antibodies, which have many drawbacks such as high costs and limited administration options. With this report, we establish an inexpensive, cell imaging-based high-throughput assay for the large-scale screening of potential small molecule complement inhibitors. Using this assay, we screened a library containing 3115 bioactive chemical compounds and identified cisplatin and pyridostatin as two new complement inhibitors in addition to nafamostat mesylate, a compound with known complement inhibitory activity. We further demonstrated that cisplatin and pyridostatin inhibit C5 convertases in the classical pathway of complement activation but have no effects on the alternative pathway of complement activation. In summary, this work has established a simple, large-scale, high-throughput assay for screening novel complement inhibitors and discovered previously unknown complement activation inhibitory activities for cisplatin and pyridostatin.



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