title: Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.
abstract: A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC50s of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT).
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors: Wenlin
authors: W
authors: Huang
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors: Zhongsheng
authors: Z
authors: Zhang
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States; Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de los Andes, Mérida, Venezuela.
authors: Ximena
authors: X
authors: Barros-Álvarez
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors: Cho Yeow
authors: CY
authors: Koh
authors: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, United States.
authors: Ranae M
authors: RM
authors: Ranade
authors: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, United States.
authors: J Robert
authors: JR
authors: Gillespie
authors: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, United States.
authors: Sharon A
authors: SA
authors: Creason
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors: Sayaka
authors: S
authors: Shibata
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors: Christophe L M J
authors: CLMJ
authors: Verlinde
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors: Wim G J
authors: WGJ
authors: Hol
authors: Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, United States. Electronic address: fbuckner@uw.edu.
authors: Frederick S
authors: FS
authors: Buckner
authors: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States. Electronic address: erkang@uw.edu.
authors: Erkang
authors: E
authors: Fan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D010539:Permeability; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D008718:Methionine-tRNA Ligase
keywords: Human African trypanosomiasis; Methionyl-tRNA synthetase; Structure-guided design