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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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Millán Elías, Cinthia Raquel
Acosta Reyes, Francisco Javier
Lagartera, Laura
Ebiloma, Godwin U.
Lemgruber, Leandro
Nué Martinez, J. Jonathan
Saperas Plana, NúriaMés informacióMés informacióMés informació
Dardonville, Cristophe
De Koning, Harry Pieter
Campos López, Josefina de LourdesMés informacióMés informació
Document typeArticle
Defense date2017-08-21
Rights accessOpen Access
Attribution-NonCommercial 3.0 Spain
Except where otherwise noted, content on this work is licensed under a Creative Commons license : Attribution-NonCommercial 3.0 Spain
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.
CitationMillan, C., Acosta-Reyes, F.J., Lagartera, L., Ebiloma, G., Lemgruber, L., Nué, J., Saperas, N., Dardonville, C., De Koning, H., Campos, J. Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast. "Nucleic acids research", 21 Agost 2017, vol. 45, núm. 14, p. 8378-8391. 
URIhttp://hdl.handle.net/2117/107671
DOI10.1093/nar/gkx521
ISSN0305-1048
Publisher versionhttps://academic.oup.com/nar/article/45/14/8378/3868900/Functional-and-structural-analysis-of-ATspecific
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