CU-CPT22 is a potent protein complex of toll-like receptor 1 and 2 (TLR1/2) inhibitor, and competes with the synthetic triacylated lipoprotein (Pam3CSK4) binding to TLR1/2 with a Ki of 0.41µM. CU-CPT22 blocks Pam3CSK4-induced TLR1/2 activation with an IC50 of 0.58µM[1].
CU-CPT22 (4-8µM) inhibited NO production in RAW 264.7 macrophages in a dose-dependent manner, and CU-CPT22 at a concentration of 8µM could inhibit approximately 60% of TNF-α and 95% of IL-1β[1]. CU-CPT22 (2-8µM) blocks the increased expression of inflammatory cytokines IL6 and TNF-α produced after TLR2 activation caused by viral infection of N9 microglia and inhibits TLR2 signaling[2].
CU-CPT22 (3mg/kg) inhibits the TLR2 pathway, improves autonomic dysfunction symptoms in MPTP mice, and protects the vagus nerve from p-α-syn-mediated myelin destruction in Parkinson’s disease[3]. In a colorectal cancer tumor model, CU-CPT22 (2.5mg/kg) significantly reduced the effect of oxaliplatin, leading to a decrease in tumor-infiltrating immune cells, including CD4+, CD8+, and IFNγ+ CD8+ cells[4]. CU-CPT22 (3mg/kg) administered before Myocardial Infarction significantly suppressed Myocardial Infarction-induced upregulation of KIM-1, TLR2, TLR4, MyD88, and chemokine (C-C motif) ligand 2 levels and activation of NF-κB, whereas NGAL levels and IL-6 and TNF-α expression levels were unchanged[5].
References:
[1]. Cheng K, Wang X, Zhang S, et al. Discovery of small molecule inhibitors of the TLR1-TLR2 complex[J]. Angewandte Chemie (International ed. in English), 2012, 51(49): 12246.
[2]. Sharma K B, Chhabra S, Aggarwal S, et al. Proteomic landscape of Japanese encephalitis virus-infected fibroblasts[J]. Journal of General Virology, 2021, 102(9): 001657.
[3]. Li Y, Tong Q, Wang Y, et al. Phosphorylated α-synuclein deposited in Schwann cells interacting with TLR2 mediates cell damage and induces Parkinson’s disease autonomic dysfunction[J]. Cell Death Discovery, 2024, 10(1): 52.
[4] Huang K C Y, Ke T W, Chen J Y, et al. Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer[J]. Scientific Reports, 2023, 13(1): 19440.
[5] Ohno K, Kuno A, Murase H, et al. Diabetes increases the susceptibility to acute kidney injury after myocardial infarction through augmented activation of renal Toll-like receptors in rats[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2017, 313(6): H1130-H1142.
CU-CPT22是一种有效的Toll样受体1和2（LR1/2）蛋白复合物抑制剂，可与合成的三酰化脂蛋白（Pam3CSK4）竞争结合TLR1/2，Ki值为0.41µM。CU-CPT22可阻断Pam3CSK4诱导的TLR1/2激活，IC50值为0.58µM[1]。
CU-CPT22（4-8µM）以剂量依赖性方式抑制RAW 264.7巨噬细胞中的NO生成，浓度为8µM的CU-CPT22可抑制约60%的TNF-α和95%的IL-1β[1]。CU-CPT22（2-8µM）可阻断病毒感染N9小胶质细胞导致的TLR2激活后产生的炎症细胞因子IL6和TNF-α表达增加，并抑制TLR2信号传导[2]。
CU-CPT22（3 mg/kg）通过抑制TLR2通路，改善MPTP小鼠的自主神经功能障碍症状，并保护迷走神经免受帕金森病中p-α-syn介导的髓鞘破坏[3]。在结直肠癌肿瘤模型中，CU-CPT22（2.5mg/kg）显着降低了奥沙利铂的治疗作用，导致肿瘤浸润，免疫细胞减少，包括CD4+、CD8+和IFNγ+ CD8+细胞[4]。在心肌梗死前注射CU-CPT22（3mg/kg）可显著抑制心肌梗死引起的KIM-1、TLR2、TLR4、MyD88和趋化因子（C-C 基序）配体2水平的上调以及NF-κB的激活，而NGAL水平和IL-6和TNF-α表达水平保持不变[5]。