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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
dc.contributor.author | Millán Elías, Cinthia Raquel |
dc.contributor.author | Acosta Reyes, Francisco Javier |
dc.contributor.author | Lagartera, Laura |
dc.contributor.author | Ebiloma, Godwin U. |
dc.contributor.author | Lemgruber, Leandro |
dc.contributor.author | Nué Martinez, J. Jonathan |
dc.contributor.author | Saperas Plana, Núria |
dc.contributor.author | Dardonville, Cristophe |
dc.contributor.author | De Koning, Harry Pieter |
dc.contributor.author | Campos López, Josefina de Lourdes |
dc.contributor.other | Universitat Politècnica de Catalunya. Departament d'Enginyeria Química |
dc.date.accessioned | 2017-09-15T13:58:31Z |
dc.date.available | 2017-09-15T13:58:31Z |
dc.date.issued | 2017-08-21 |
dc.identifier.citation | Millan, 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.issn | 0305-1048 |
dc.identifier.uri | http://hdl.handle.net/2117/107671 |
dc.description.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. |
dc.format.extent | 14 p. |
dc.language.iso | eng |
dc.rights | Attribution-NonCommercial 3.0 Spain |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/3.0/es/ |
dc.subject | Àrees temàtiques de la UPC::Enginyeria química |
dc.subject.lcsh | Cell cycle |
dc.subject.lcsh | Trypanosoma brucei |
dc.subject.other | cell cycle dna dna |
dc.subject.other | kinetoplast trypanosoma brucei brucei mice kinetoplast crystal structure |
dc.title | Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast |
dc.type | Article |
dc.subject.lemac | Cicle cel·lular |
dc.subject.lemac | Tripanosomes |
dc.contributor.group | Universitat Politècnica de Catalunya. MACROM - Cristal·lografia, Estructura i Funció de Macromolècules Biològiques |
dc.identifier.doi | 10.1093/nar/gkx521 |
dc.relation.publisherversion | https://academic.oup.com/nar/article/45/14/8378/3868900/Functional-and-structural-analysis-of-ATspecific |
dc.rights.access | Open Access |
local.identifier.drac | 21478150 |
dc.description.version | Postprint (published version) |
local.citation.author | Millan, C.; Acosta-Reyes, F.J.; Lagartera, L.; Ebiloma, G.; Lemgruber, L.; Nué, J.; Saperas, N.; Dardonville, C.; De Koning, H.; Campos, J.Lourdes |
local.citation.publicationName | Nucleic acids research |
local.citation.volume | 45 |
local.citation.number | 14 |
local.citation.startingPage | 8378 |
local.citation.endingPage | 8391 |
dc.identifier.pmid | 28637278 |
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