Targeting CD38/ ADP-ribosyl cyclase as a novel therapeutic strategy for identification of three potent agonists for leukopenia treatment

• DOI: 10.1016/j.phrs.2024.107068
• Publication Date: 2024-01-15T17:17:57Z
• Authors: Yuanzhi Liu; Linwei Zhang; Long Wang; Xiaoqin Tang; Shengli Wan; Qianqian Huang; Mei Ran; Hongping Shen; Yan Yang; Sawitree Chiampan...; Singkome Tima; Songyot Anuchapreeda; Jianming Wu
• Keywords: Leukopenia

Leukopenia is the most common side effect of chemotherapy and radiotherapy. It potentially deteriorates into a life-threatening complication in cancer patients. Despite several agents being approved for clinical administration, there are still high incidences pathogen-related disease due to lack functional immune cells. ADP-ribosyl cyclase CD38 displays regulatory on leukopoiesis system. To explore whether was potential therapeutic target leukopenia. We established drug screening model based an cyclase-based pharmacophore generation algorithm discovered three novel agonists: ziyuglycoside II (ZGSII), brevifolincarboxylic acid (BA), 3,4-dihydroxy-5-methoxybenzoic (DMA). Then, vitro experiments demonstrated that these natural compounds significantly promoted myeloid differentiation antibacterial activity NB4 In vivo, confirmed also stimulated recovery leukocytes irradiation-induced mice zebrafish. The mechanism investigated by network pharmacology, top 12 biological processes 20 signaling pathways were obtained intersecting genes among ZGSII, BA, DNA, molecules involved further explored through experiments. Finally, agonists (ZGSII, DMA) has been found regenerate microbicidal cells effectively ameliorate leukopenia-associated infection activating CD38/cyclic ADP-ribose-Ca2+-NFAT. summary, this study constructs discover active against leukopenia, reveals critical roles promoting response, provides promising strategy treatment radiation-induced