2. Academic Validation
  3. DNA G-quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: Dithienylethene ligands as effective antiparasitic agents

DNA G-quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: Dithienylethene ligands as effective antiparasitic agents

  • Eur J Med Chem. 2024 Oct 5:276:116641. doi: 10.1016/j.ejmech.2024.116641.
Manuel Pérez-Soto 1,  Javier Ramos-Soriano 2,  Pablo Peñalver 1,  Efres Belmonte-Reche 3,  Michael P O'Hagan 2,  Anne Cucchiarini 4,  Jean-Louis Mergny 4,  M Carmen Galán 5,  Manuel Carlos López López 6,  María Del Carmen Thomas 7,  Juan Carlos Morales 8
Affiliations

Affiliations

  • 1 Departamento de Biología Molecular, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avenida Del Conocimiento, 17, Armilla, 18016 Granada, Spain.
  • 2 School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
  • 3 GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada / Andalusian Regional Government, PTS Granada, Av. de La Ilustración, 114, 18016 Granada, Spain; Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria Ibs.GRANADA, Hospital Virgen de Las Nieves, Granada, Spain.
  • 4 Laboratoire d'optique et Biosciences, Ecole Polytechnique, Inserm U1182, CNRS UMR7645, Institut Polytechnique de Paris, Palaiseau, France.
  • 5 School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom. Electronic address: [email protected].
  • 6 Departamento de Biología Molecular, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avenida Del Conocimiento, 17, Armilla, 18016 Granada, Spain. Electronic address: [email protected].
  • 7 Departamento de Biología Molecular, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avenida Del Conocimiento, 17, Armilla, 18016 Granada, Spain. Electronic address: [email protected].
  • 8 Departamento de Biología Molecular, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avenida Del Conocimiento, 17, Armilla, 18016 Granada, Spain. Electronic address: [email protected].
PMID: 38971047 DOI: 10.1016/j.ejmech.2024.116641
Abstract

Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5-3.3 μM, SI = 25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.

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