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dc.contributor.authorMillán Elías, Cinthia Raquel
dc.contributor.authorAcosta Reyes, Francisco Javier
dc.contributor.authorLagartera, Laura
dc.contributor.authorEbiloma, Godwin U.
dc.contributor.authorLemgruber, Leandro
dc.contributor.authorNué Martinez, J. Jonathan
dc.contributor.authorSaperas Plana, Núria
dc.contributor.authorDardonville, Cristophe
dc.contributor.authorDe Koning, Harry Pieter
dc.contributor.authorCampos López, Josefina de Lourdes
dc.contributor.otherUniversitat Politècnica de Catalunya. Departament d'Enginyeria Química
dc.date.accessioned2017-09-15T13:58:31Z
dc.date.available2017-09-15T13:58:31Z
dc.date.issued2017-08-21
dc.identifier.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.
dc.identifier.issn0305-1048
dc.identifier.urihttp://hdl.handle.net/2117/107671
dc.description.abstractTrypanosoma 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.
dc.format.extent14 p.
dc.language.isoeng
dc.rightsAttribution-NonCommercial 3.0 Spain
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/es/
dc.subjectÀrees temàtiques de la UPC::Enginyeria química
dc.subject.lcshCell cycle
dc.subject.lcshTrypanosoma brucei
dc.subject.othercell cycle dna dna
dc.subject.otherkinetoplast trypanosoma brucei brucei mice kinetoplast crystal structure
dc.titleFunctional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast
dc.typeArticle
dc.subject.lemacCicle cel·lular
dc.subject.lemacTripanosomes
dc.contributor.groupUniversitat Politècnica de Catalunya. MACROM - Cristal·lografia, Estructura i Funció de Macromolècules Biològiques
dc.identifier.doi10.1093/nar/gkx521
dc.relation.publisherversionhttps://academic.oup.com/nar/article/45/14/8378/3868900/Functional-and-structural-analysis-of-ATspecific
dc.rights.accessOpen Access
drac.iddocument21478150
dc.description.versionPostprint (published version)
upcommons.citation.authorMillan, C., Acosta-Reyes, F.J., Lagartera, L., Ebiloma, G., Lemgruber, L., Nué, J., Saperas, N., Dardonville, C., De Koning, H., Campos, J.Lourdes
upcommons.citation.publishedtrue
upcommons.citation.publicationNameNucleic acids research
upcommons.citation.volume45
upcommons.citation.number14
upcommons.citation.startingPage8378
upcommons.citation.endingPage8391


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