Small Molecule-Peptide Conjugates as Dimerization Inhibitors of Leishmania infantum Trypanothione Disulfide Reductase

  • Pharmaceuticals (Basel). 2021 Jul 17;14(7):689. doi: 10.3390/ph14070689.
Alejandro Revuelto  1 ,  Isabel López-Martín  1 ,  Héctor de Lucio  2 ,  Juan Carlos García-Soriano  2 ,  Nicola Zanda  1 ,  Sonia de Castro  1 ,  Federico Gago  3 ,  Antonio Jiménez-Ruiz  2 ,  Sonsoles Velázquez  1 ,  María-José Camarasa  1
Affiliations
  • 1. Instituto de Química Médica (IQM-CSIC), E-28006 Madrid, Spain.
  • 2. Departamento de Biología de Sistemas, Universidad de Alcalá, E-28805 Alcalá de Henares, Spain.
  • 3. Unidad Asociada al IQM-CSIC, Área de Farmacología, Departamento de Ciencias Biomédicas, Universidad de Alcalá, E-28805 Alcalá de Henares, Spain.
PMID: 34358115 DOI: 10.3390/ph14070689
Abstract

Trypanothione disulfide reductase (TryR) is an essential homodimeric enzyme of trypanosomatid parasites that has been validated as a drug target to fight human infections. Using peptides and peptidomimetics, we previously obtained proof of concept that disrupting protein-protein interactions at the dimer interface of Leishmania infantum TryR (LiTryR) offered an innovative and so far unexploited opportunity for the development of novel antileishmanial agents. Now, we show that linking our previous peptide prototype TRL38 to selected hydrophobic moieties provides a novel series of small-molecule-peptide conjugates that behave as good inhibitors of both LiTryR activity and dimerization.

Keywords
dimerization inhibitors; leishmaniasis; small molecule–peptide conjugates; trypanothione disulfide reductase.