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Inhibition of the C1s Protease and the Classical Complement Pathway by 6-(4-Phenylpiperazin-1-yl)Pyridine-3-Carboximidamide and Chemical Analogs

J Immunol. 2024-02; 
Xin Xu, Timothy J Herdendorf, Huiquan Duan, Denise L Rohlik, Sourav Roy, Hinman Zhou, Haya Alkhateeb, Sanjay Khandelwal, Qilong Zhou, Ping Li, Gowthami M Arepally, John K Walker, Brandon L Garcia, Brian V Geisbrecht
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Recombinant Proteins … of the C1s-2SP (recombinant C1s fragment containing the second CCP domain and the SP domain) region of human C1s in HEK293T cells was also obtained from GenScript. A gene … Get A Quote

摘要

The classical pathway (CP) is a potent mechanism for initiating complement activity and is a driver of pathology in many complement-mediated diseases. The CP is initiated via activation of complement component C1, which consists of the pattern recognition molecule C1q bound to a tetrameric assembly of proteases C1r and C1s. Enzymatically active C1s provides the catalytic basis for cleavage of the downstream CP components, C4 and C2, and is therefore an attractive target for therapeutic intervention in CP-driven diseases. Although an anti-C1s mAb has been Food and Drug Administration approved, identifying small-molecule C1s inhibitors remains a priority. In this study, we describe 6-(4-phenylpiperazin-1-yl)pyrid... More

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