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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.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2017 Aug 21; Vol. 45 (14), pp. 8378-8391. - Publication Year :
- 2017
-
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.<br /> (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Animals
Binding Sites genetics
Crystallography, X-Ray
DNA, Kinetoplast chemistry
DNA, Kinetoplast metabolism
Humans
Mice
Nucleic Acid Conformation
Protein Binding
Protozoan Proteins chemistry
Protozoan Proteins metabolism
Surface Plasmon Resonance
Trypanocidal Agents chemistry
Trypanocidal Agents metabolism
Trypanocidal Agents pharmacology
Trypanosoma brucei brucei drug effects
Trypanosoma brucei brucei metabolism
Trypanosomiasis, African drug therapy
Trypanosomiasis, African parasitology
Base Pairing
DNA, Kinetoplast genetics
Protozoan Proteins genetics
Trypanosoma brucei brucei genetics
Trypanosomiasis, African metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 45
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 28637278
- Full Text :
- https://doi.org/10.1093/nar/gkx521