Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610106, China.
Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu 610065, China.
Curr Protein Pept Sci. 2021 Oct 26;22(4):290-303. doi: 10.2174/1389203722666210421105733.
Tuberculosis (TB) remains a serious threat to whole human health. In particular, the drug resistance of Mycobacterium tuberculosis (Mtb) has become a huge challenge in clinical medicine, and it is extremely urgent to develop effective inhibitors with novel structures and mechanisms. Belonging to the Resistance, Nodulation and Division (RND) superfamily, Mycobacterial membrane proteins Large 3 (MmpL3) is mainly responsible for transporting mycolic acid outside cell membrane to form cell wall, and plays critical roles in iron acquisition which is vital to the survival of Mtb. As a potential Mtb target in recent years, its inhibitor research has attracted wide attention. A series of inhibitors (such as SQ109, AU1235, BM212, etc.) through experimental screening have been reported in succession, especially SQ109 has entered the clinical stage. In this paper, the structural biology information of target MmpL3 was summarized, and the structure-activity relationship (SAR) of inhibitors reported in recent years and their inhibitory mechanism both were reviewed, aiming to provide help for the rational design of MmpL3 inhibitors in the future.
结核病（TB）仍然对全人类的健康构成严重威胁。特别是结核分枝杆菌（Mtb）的耐药性已成为临床医学中的一个巨大挑战，因此迫切需要开发具有新颖结构和机制的有效抑制剂。属于抗性、结节和分裂（RND）超家族的分枝杆菌膜蛋白大 3（MmpL3）主要负责将分枝菌酸运出细胞膜以形成细胞壁，并在铁摄取中发挥关键作用，铁摄取对 Mtb 的生存至关重要。作为近年来潜在的 Mtb 靶标，其抑制剂的研究受到了广泛关注。已经相继报道了一系列通过实验筛选的抑制剂（如 SQ109、AU1235、BM212 等），特别是 SQ109 已进入临床阶段。本文总结了目标 MmpL3 的结构生物学信息，并综述了近年来报道的抑制剂的构效关系（SAR）及其抑制机制，旨在为未来 MmpL3 抑制剂的合理设计提供帮助。
