Synthesis and characterization of I-BET151 derivatives for use in identifying protein targets in the African trypanosome
Year: 2023
Type: article
Abstract: Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT) and animal trypanosomiases, cycles between a bloodstream form in mammals and a procyclic form in the gut of its insect vector. We previously discovered that the human bromodomain inhibitor I-BET151 causes transcriptome changes that resemble the transition from the bloodstream to the procyclic form. In particular, I-BET151 induces replacement of variant surface glycoprotein (VSG) with procyclin protein. While modest binding of I-BET151 to TbBdf2 and TbBdf3 has been demonstrated, it is unknown whether I-BET151 binds to other identified T. brucei bromodomain proteins and/or other targets. To identify target(s) in T. brucei, we have synthesized I-BET151 derivatives maintaining the key pharmacophoric elements with functionality useful for chemoproteomic approaches. We identified compounds that are potent in inducing expression of procyclin, delineating a strategy towards the design of drugs against HAT and other trypanosomiases. Furthermore, these derivatives represent useful chemical probes to elucidate the molecular mechanism underlying I-BET151-induced differentiation.
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $1,850
Awards: G1390870092, Target Validation for I-BET151-Induced Differentiation in the African Trypanosome, G5105808139, Purchase of an Echo 650 acoustic liquid handler with Access workstation, A NEW HYBRID DIFFRACTOMETER FOR MACROMOLECULAR CRYSTALLOGRAPHY AND SAXS AT TJU, G9000231672, G9000307965, G9000340205, Chromatin Biology of the African Trypanosome, Translational Research in Cancer, Consolidated Basic Cancer Research Program, G985716880
OpenAlex ID: W4388447362