双向调控模式识别受体（PRRs）逆转肿瘤化疗抵抗的药物分子设计

化疗抵抗是临床癌症治疗失败的最主要原因，肿瘤微环境（TME）可介导肿瘤获得性耐药并抵抗化疗所致的细胞凋亡。模式识别受体（PRRs）对TME介导的化疗抵抗具有双向调控的作用，一方面NOD1/2等PRRs识别TME中化疗所致的损伤相关模式分子（DAMPs），激活下游炎症通路，促进TME重塑，导致肿瘤的药物抵抗；另一方面，TLR7等PRRs介导浆细胞样树突状细胞（pDCs）的活化，释放I型干扰素（Type I IFNs），打破TME中的免疫耐受。本项目拟利用耐药肿瘤动物模型，在拮抗NOD1/2的基础上，同步激动TLR7，探讨双向调控PRRs在化疗所致TME介导的药物抵抗过程中的作用机制以及打破肿瘤化疗TME抵抗的条件；并运用多靶点药物分子设计的策略，合成并筛选得到新型双靶点小分子药物候选物，实现单一化合物双向调节不同PRRs逆转肿瘤化疗抵抗的目的。

Chemo-resistance is the main cause for the failure of clinical cancer treatment. Acquired chemo-resistance can be mediate by tumor microenvironment (TME), in which tumor cells are protected from apoptosis induced by the chemotherapy. Pattern recognition receptors (PRRs) are bifacial in the regulation of TME mediated chemo-resistance. NOD1/2 signaling activated by DAMPs can induce production of inflammation cytokines and TME remodeling, resulting in chemo-resistance. In contrast, activation of TLR7 in plasmacytoid dendritic cells (pDCs) can overcome immune tolerance by releasing type I IFNs. In this project, chemo-resistance tumor bearing mice will be treated by NOD1/2 antagonist combined with TLR7 agonist. The molecular mechanisms underlying targeting different PRRs to reverse tumor resistance against chemotherapy will be explored. By using the strategy of designed multiple ligands (DMLs), novel bifunctional drug candidates that can both inhibit NOD1/2 and activate TLR7 signaling will be designed, synthesized, screened and investigated. Reversing chemo-resistance by modulating different PRRs in one single molecule will finally achieved.