ArticleNucleic acids research2017
Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast.
Article in Nucleic acids research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Direct amidinium-phosphate interactions guide AT-selective DNA binding by a potent antileishmanial drug.Communications chemistry · 2026Article
- Guanidines: Privileged Scaffolds Against Neglected Tropical Diseases: A Review.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Kinetoplast-Directed Therapies: A Selective Mitochondrial Approach to Combat Leishmaniasis.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Nanostructured Lipid Carrier for Intracellular Delivery of a Bis(pyridine-2-carboxamidine) DNA Minor Groove Binder Active againstACS omega · 2025Article
- Crystal structure of the HMGA AT-hook 1 domain bound to the minor groove of AT-rich DNA and inhibition by antikinetoplastid drugs.Scientific reports · 2024Article
- Synthesis and Biophysical and Biological Studies ofJournal of medicinal chemistry · 2023Article
- Enabling programmable dynamic DNA chemistry using small-molecule DNA binders.Nature communications · 2023Article
- COVID-19 and Diarylamidines: The Parasitic Connection.International journal of molecular sciences · 2023Review
- Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure-Activity Relationship Studies.ACS medicinal chemistry letters · 2022Article
- Synthesis, antiproliferative and antitrypanosomal activities, and DNA binding of novel 6-amidino-2-arylbenzothiazoles.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Elucidating the possible mechanism of action of some pathogen box compounds against Leishmania donovani.PLoS neglected tropical diseases · 2020Article
- Investigation of 5'-Norcarbocyclic Nucleoside Analogues as Antiprotozoal and Antibacterial Agents.Molecules (Basel, Switzerland) · 2019Article
- Evolutionary Insight into the Trypanosomatidae Using Alignment-Free Phylogenomics of the Kinetoplast.Pathogens (Basel, Switzerland) · 2019Article
- A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis.PLoS neglected tropical diseases · 2019Article
- Article
- A New Generation of Minor-Groove-Binding-Heterocyclic Diamidines That Recognize G·C Base Pairs in an AT Sequence Context.Molecules (Basel, Switzerland) · 2019Review
- Recent developments in compounds acting in the DNA minor groove.MedChemComm · 2019Review
- Drug resistance in protozoan parasites.Emerging topics in life sciences · 2017Article
- A modular design for minor groove binding and recognition of mixed base pair sequences of DNA.Chemical communications (Cambridge, England) · 2017Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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