Τίτλος:
Indirubin analogues inhibit trypanosoma brucei glycogen synthase kinase 3 short and T. Brucei growth
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT). The disease is fatal if it remains untreated, whereas most drug treatments are inadequate due to high toxicity, difficulties in administration, and low central nervous system penetration. T. brucei glycogen synthase kinase 3 short (TbGSK3s) is essential for parasite survival and thus represents a potential drug target that could be exploited for HAT treatment. Indirubins, effective leishmanicidals, provide a versatile scaffold for the development of potent GSK3 inhibitors. Herein, we report on the screening of 69 indirubin analogues against T. brucei bloodstream forms. Of these, 32 compounds had potent antitrypanosomal activity (half-maximal effective concentration 0.050 to 3.2 M) and good selectivity for the analogues over human HepG2 cells (range, 7.4- to over 641-fold). The majority of analogues were potent inhibitors of TbGSK3s, and correlation studies for an indirubin subset, namely, the 6-bromosubstituted 3=-oxime bearing an extra bulky substituent on the 3= oxime [(6-BIO-3=-bulky)-substituted indirubins], revealed a positive correlation between kinase inhibition and antitrypanosomal activity. Insights into this indirubin-TbGSK3s interaction were provided by structure-activity relationship studies. Comparison between 6-BIO-3=-bulky-substituted indirubin-treated parasites and parasites silenced for TbGSK3s by RNA interference suggested that the above-described compounds may target TbGSK3s in vivo. To further understand the molecular basis of the growth arrest brought about by the inhibition or ablation of TbGSK3s, we investigated the intracellular localization of TbGSK3s. TbGSK3s was present in cytoskeletal structures, including the flagellum and basal body area. Overall, these results give insights into the mode of action of 6-BIO-3=-bulky-substituted indirubins that are promising hits for antitrypanosomal drug discovery. Copyright © 2019 American Society for Microbiology. All Rights Reserved.
Συγγραφείς:
Efstathiou, A.
Gaboriaud-Kolar, N.
Myrianthopoulos, V.
Vougogiannopoulou, K.
Subota, I.
Aicher, S.
Mikros, E.
Bastin, P.
Skaltsounis, A.-L.
Soteriadou, K.
Smirlis, D.
Περιοδικό:
Antimicrobial Agents and Chemotherapy
Εκδότης:
American Society for Microbiology
Λέξεις-κλειδιά:
6 bromosubstituted 3' oxime; arginine glutamate; aurora kinase; glycogen synthase kinase 3; glycogen synthase kinase 3beta; indirubin; unclassified drug; antitrypanosomal agent; glycogen synthase kinase 3; indirubin; indole derivative; protein kinase inhibitor, antitrypanosomal activity; Article; bacterial growth; baculovirus expression system; bloodstream infection; cell cycle arrest; cell death; chemical composition; comparative study; controlled study; cytoskeleton; drug screening; EC50; flagellum; gene expression; gene silencing; growth disorder; Hep-G2 cell line; human; human cell; in vivo study; kinetosome; priority journal; RNA interference; structure activity relation; trypanocidal activity; Trypanosoma brucei; African trypanosomiasis; animal; cell line; drug effect; insect; metabolism; parasitology; Trypanosoma brucei brucei, Animals; Cell Line; Glycogen Synthase Kinase 3; Indoles; Insecta; Protein Kinase Inhibitors; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African
DOI:
10.1128/AAC.02065-18
