角鲨烯合成酶 z-bo 2020-11-03 367

　　African trypanosomiasis, also known as African sleep sickness or sleepiness encephalitis, is a zoonotic parasitic disease transmitted by trypanosomes through the bite of tsetse flies. It rages in sub-Saharan Africa, with high prevalence in some endemic areas 80%. At present, the development of new anti-infective drugs by blocking the endogenous sterol synthesis pathway of these trypanosomes is an international research hotspot.

　　Recently, the research group led by researcher Guo Ruiting of the Tianjin Institute of Industrial Biotechnology of the Chinese Academy of Sciences and the research group of Professor Eric Oldfield of UIUC University obtained the crystal structure of the enzyme protein of squalene synthase (TcSQS) derived from Trypanosoma cruzi for the first time. A total of 13 TcSQS and human squalene synthase (HsSQS) complex structures with substrates and inhibitors were obtained. These include substrate analogs, E5700 and ER119884 with quinuclidine structure, lipophilic diphosphates BPH1218, BPH1237, BPH1325 and BPH1344, and thiocyanate WC-9. Two of the inhibitors with quinuclidine have good selectivity and are the development direction of inhibitors. In addition, the lipophilic bisphosphate inhibitor has a highly effective inhibitory effect on the squalene synthase of trypanosomes, and the inhibitor E5700 also has a good synergistic effect with azole drugs (such as posaconazole).

　　Obtaining the complex crystal structure of TcSQS/HsSQS substrate and its inhibitors can understand the catalytic mechanism of enzyme proteins and the binding sites of these inhibitors and proteins, providing a solid foundation for the research of squalene synthase inhibitors. It also provides ideas for the development of drugs for the treatment of sleep diseases in Africa.

　　research results have been accepted by the top microbial journal PLOS Pathogen. Assistant researchers Shang Na and Li Qian of Tianjin Institute of Industrial Biology are the co-first authors of this article. This project is supported by the 863 Project and the 973 Project.