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Title: | Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast |
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Author: | Millán Elías, Cinthia Raquel; Acosta Reyes, Francisco Javier; Lagartera, Laura; Ebiloma, Godwin U.; Lemgruber, Leandro; Nué Martinez, J. Jonathan; Saperas Plana, Núria; Dardonville, Cristophe; De Koning, Harry Pieter; Campos López, Josefina de Lourdes |
Other authors: | Universitat Politècnica de Catalunya. Departament d'Enginyeria Química; Universitat Politècnica de Catalunya. MACROM - Cristal·lografia, Estructura i Funció de Macromolècules Biològiques |
Abstract: | Trypanosoma brucei, the causative agent of sleeping sickness (Human African Trypanosomiasis, HAT), contains a kinetoplast with the mitochondrial DNA (kDNA), comprising of >70% AT base pairs. This has prompted studies of drugs interacting with AT-rich DNA, such as the N-phenylbenzamide bis(2-aminoimidazoline) derivatives 1 [4-((4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide dihydrochloride] and 2 [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2-yl)amino)benzamide] as potential drugs for HAT. Both compounds show in vitro effects against T. brucei and in vivo curative activity in a mouse model of HAT. The main objective was to identify their cellular target inside the parasite. We were able to demonstrate that the compounds have a clear effect on the S-phase of T. brucei cell cycle by inflicting specific damage on the kinetoplast. Surface plasmon resonance (SPR)–biosensor experiments show that the drug can displace HMG box-containing proteins essential for kDNA function from their kDNA binding sites. The crystal structure of the complex of the oligonucleotide d[AAATTT]2 with compound 1 solved at 1.25 Å (PDB-ID: 5LIT) shows that the drug covers the minor groove of DNA, displaces bound water and interacts with neighbouring DNA molecules as a cross-linking agent. We conclude that 1 and 2 are powerful trypanocides that act directly on the kinetoplast, a structure unique to the order Kinetoplastida. |
Subject(s): | -Àrees temàtiques de la UPC::Enginyeria química -Cell cycle -Trypanosoma brucei -cell cycle dna dna -kinetoplast trypanosoma brucei brucei mice kinetoplast crystal structure -Cicle cel·lular -Tripanosomes |
Rights: | Attribution-NonCommercial 3.0 Spain
http://creativecommons.org/licenses/by-nc/3.0/es/ |
Document type: | Article - Published version Article |
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