Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast

Cinthia R. Millan, Francisco J. Acosta-Reyes, Laura Lagartera, Godwin U. Ebiloma, Leandro Lemgruber, J. Jonathan Nué Martínez, Núria Saperas, Christophe Dardonville, Harry P. De Koning, J. Lourdes Campos

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26 Citas (Scopus)


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 [4-((4, 5-dihydro-1Himidazol- 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 °A (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.
Idioma originalEspañol
Páginas (desde-hasta)8378-8391
Número de páginas14
PublicaciónNucleic Acids Research
EstadoPublicada - 21 ago. 2017
Publicado de forma externa

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